Compounds for treating disorders mediated by metabotropic glutamate receptor 5, and methods of use thereof

ABSTRACT

Provided herein are compounds and methods of synthesis thereof. The compounds set forth herein are useful for the treatment, prevention, and/or management of various disorders, such as neurological disorders, neurodegenerative disorders, neuropsychiatric disorders, disorders of cognition, learning or memory, gastrointestinal disorders, lower urinary tract disorder, and cancer. Compounds set forth herein modulate the activity of metabotropic glutamate receptor 5 (mGluR5) in the central nervous system or the periphery. Pharmaceutical formulations containing the compounds and their methods of use are also provided herein.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/288,250, filed Dec. 18, 2009. The entire contents of theforegoing application are hereby incorporated by reference.

FIELD

Provided herein are compounds useful for treating disorders mediated bymetabotropic glutamate receptor 5 (mGluR5), compositions comprising thecompounds, and methods of use thereof.

BACKGROUND

The amino acid L-glutamate (which herein is referred to simply asglutamate) is the principal excitatory neurotransmitter in the brain andother elements of the central nervous system of mammals. Glutamate bindsto neurons and activates cell surface receptors. Glutamate hassignificant roles in motor control, cognitive function, sensoryperception, and acts as a mediator of persistent changes in the strengthof synaptic signaling (synaptic plasticity), thereby modulating longterm potentiation (LTP) and long term depression (LTD), which form thebasis of learning and memory. Many neurological and neuropsychiatricdisorders, including, but not limited to, psychosis spectrum disorders,schizophrenia and other cognitive deficits, are associated withaberrations in the function of (or the regulation by, or the regulationof) glutamate signaling systems.

Glutamate acts through two heterogeneous families of receptors:ionotropic and metabotropic glutamate receptors (mGluR). mGluRs are Gprotein-coupled receptors that activate intracellular second messengerswhen bound to glutamate. Eight subtypes of mGluRs have been cloned andclassified into three groups on the basis of sequence similarities andpharmacological properties. mGluR1 and mGluR5 belong to Group I, whichinitiate cellular responses through a G-protein mediated mechanism andactivate phospholipase C, leading to phosphoinositide hydrolysis and themobilization of intracellular calcium (Schoepp, D. D., et al.,Neuropharmacology 1999, 38, 1431). Two receptors that are central to thecurrent understanding of new approaches for the treatment of theforegoing neurological and neuropsychiatric disorders are (i) anionotropic glutamate receptor, namely the NMDA receptor [reviewed inStahl, S. M. (2007) CNS Spectrum 12: 583-588], and (ii) mGluR5 [reviewedin Lindsley, C. W. et al. (2006) Current Topics in Medicinal Chemistry6: 771-885; Pietraszek, M. et al. (2007) Amino Acids 32: 173-178]. Asalient aspect of this understanding is that reduced function(hypofunction) of the NMDA receptor is involved in the symptoms ofpsychotic and schizophrenic diseases and disorders [Stahl, S. M. (2007)CNS Spectrum 12: 583-588]. Since activation of mGluR5 causes activationof the NMDA receptors that are present post-synaptically in the samecells, the exposure of the CNS to a positive allosteric modulator ofmGluR5 may lead to increases in neuronal ion currents (and increasedsynaptic circuit firing) dependent upon the NMDA receptor [Lecourtier,L. et al. (2007) Biological Psychiatry 62:739-746; Uslaner, J. M. et al.(2009) Neuropharmacology 57: 531-538], as well as to behavioral changesthat may indicate antipsychotic and pro-cognitive activities [Liu, F. etal. (2008) J. Pharmacol. Exp. Ther. 327: 827-839; Kinney, G. G. et al.(2005) J. Pharmacol. Exp. Ther. 313: 199-206]. Positive allostericmodulators of mGluR5 therefore may be of benefit in the treatment ofpsychotic, schizophrenic, cognitive and related neurological andneuropsychiatric diseases, either alone, or as adjunctive therapiescombined with other treatments.

Moreover, since mGluR5 is expressed in both the central nervous systemand the periphery (Chizh, B. A., et al., Amino Acids 2002, 23, 169),modulation of mGluR5 activity may be useful in the treatment of bothperipheral and CNS disorders. With respect to peripheral disorders,mGluR5 negative allosteric modulators have shown efficacy in thetreatment of gastrointestinal (GI) tract disorders, such asgastroesophageal reflux disease (GERD).

In the CNS, excessive activation of mGluR5 has been implicated in anumber of diseases, such as various pain states, neuropsychiatricdisorders such as anxiety and depression, and other neurologicalimpairments such as drug addiction and drug withdrawal. For example,mGluR5 negative allosteric modulators are efficacious in the treatmentof anxiety in a variety of animal models, including stress-inducedhyperthermia and fear-potentiated startle.

Migraine is another CNS disorder relevant to mGluR5 modulation. Migraineis a chronic debilitating condition characterized by recurrent severeheadaches that are often accompanied by a variety of other symptoms,such as nausea and fatigue. Pharmacologic therapies for the treatment ofmigraine may be divided into two classes, acute therapies for thetreatment of symptoms when they arise, and chronic therapies designed toprevent the onset of migraine (prophylactics) (Goadsby, P. J., et al.,N. Engl. J. Med. 2002, 346, 257). The best known therapeutics for thetreatment of acute migraine are triptans, dual 5-HT_(1b)/5-HT_(1d)agonists that exert their therapeutic effects through cranialvasoconstriction. Although generally well-tolerated, their use isrestricted in the presence of cardiovascular disease due to their5-HT_(1b) agonism.

In contrast to the treatment for acute attacks, the current therapiesfor migraine prophylaxis may be subdivided into three classes:β-blockers, anticonvulsants, and antidepressants. All are moderatelyeffective and carry substantial side-effects. Most prominent among theβ-blockers is propranolol, whose side-effects include lethargy andhypotension. Valproate and topiramate are the most commonly usedanticonvulsants, but, like the antidepressants, they cause side-effectssuch as fatigue. There is a clear medical need for a novel prophylactictherapy that is effective and free from the side-effects. Recently, anmGluR5 antagonist demonstrated efficacy in treating acute migraine inhuman clinical trials. The robust anxiolytic and antidepressantactivities of mGluR5 antagonists should be beneficial to migrainepatients, who often suffer anxiety and depression.

Other peripheral and CNS disorders relevant to mGluR5 modulation includeschizophrenia, neurodegenerative diseases, levodopa-induced dyskinesia,fragile X syndrome, substance abuse/addiction, epilepsy, inflammatory,visceral and neuropathic pain, and post-traumatic stress disorder.Therefore, there is a need for effective mGluR5 modulators astherapeutics for the treatment of the aforementioned disorders.

SUMMARY

The present invention is based, at least in part, on the discovery thatthe compounds as disclosed herein are allosteric modulators of mGluR5,for example negative or positive allosteric modulators. Accordingly, insome aspects, the invention provides compounds of formula (I), orpharmaceutically acceptable salts, solvates, or stereoisomers thereof:

In various embodiments, a compound of formula (I) is provided:

wherein;

R¹ is hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, arylor heteroaryl, each of which is optionally substituted;

R² is hydrogen, lower alkyl, lower alkenyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl,alkylheteroaryl, aryl, heteroaryl, —C(O)OR¹², or —CO—NR¹², each of whichis optionally substituted;

R³ is hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, arylor heteroaryl, each of which is optionally substituted; or

R² and R³ are optionally joined, together with the atoms to which theyare attached, to form a mono or bicyclic ring that is carbocyclic orheterocyclic, each of which is optionally substituted;

G is CHR² or NR² when b and c are both single bonds, or G is CR² or Nwhen one of b and c is a double bond;

Q is NH or CH₂ when d and e are single bonds, or N or CH when one of dor e is a double bond, or;

X is CH or N when f is a single bond, or C when f is a double bond;

Z is CH₂, C═O, C═S or a bond when b is a single bond, or CH or N when bis a double bond;

b, c, d, e, and f are each independently a single bond or a double bond,provided that when b is a double bond, c is a single bond; when c is adouble bond, b and d are single bonds; when d is a double bond, c and eare single bonds; when e is a double bond, d and f are single bonds; andwhen f is a double bond, e is a single bond;

Y¹, Y² and Y³ are each independently CH, C-halogen, C-lower alkyl, or N,provided that no more than one of Y² and Y³ is N;

L¹ is —C≡C—, —HC═CH—, -(lower alkyl)C═C(lower alkyl)-, —CH₂—CH₂—,—CO—CH₂—, —CH(OH)—CH₂, —CH₂—CO—, —C₀₋₆alkyl-O—C₀₋₆alkyl-, —NR¹²SO—,—SONR¹²—, —NR¹²SO₂—, —SO₂NR¹²—, —NR¹²—CO—, —CO—NR¹²—,

R¹² is hydrogen or lower alkyl;

W¹ and W² are each independently N or CH;

W³ is O, S or NR⁴; and

R⁴ is hydrogen or lower alkyl;

or a pharmaceutically acceptable salt thereof;

provided that at least one of c and d is a double bond.

In one embodiment, at least one of G, Q, and X is a nitrogen atom. Inone embodiment, at least two of G, Q, and X is a nitrogen atom. In oneembodiment, both Q and G are nitrogen atoms. In one embodiment, both Qand X are nitrogen atoms.

In some aspects, the present invention provides pharmaceuticalcompositions and dosage forms comprising the compounds as disclosedherein. Compositions and dosage forms may comprise one or moreadditional active ingredients.

In some embodiments, methods are provided for the treatment ofneurological disorders, such as neurodegenerative diseases,neuropsychiatric diseases, affective disorders, and loss of cognitivefunction, learning and memory disorders.

In some embodiments, methods are provided for the treatment, prevention,and/or management of psychosis.

In some embodiments, methods are provided for the treatment, prevention,and/or management of schizophrenia.

In some embodiments, methods are provided for the treatment, prevention,and/or management of Alzheimer's disease.

In some embodiments, methods are provided for the treatment, prevention,and/or management of cognitive disorders.

In some aspects, methods are provided for the treatment, prevention,and/or management of various conditions, disorders, or diseases mediatedby mGluR5 using the compounds and compositions provided herein.

In some aspects, methods of modulating the activity of mGluR5 areprovided. The method comprises contacting mGluR5 with an effectiveamount of a compound as disclosed herein.

In some aspects, methods of inhibiting or reducing the activity ofmGluR5 are provided. The method comprises contacting mGluR5 in a cell orin a subject with an effective amount of an antagonist or a negativeallosteric modulator.

In some aspects, methods of potentiating, augmenting, or increasing theactivity of mGluR5 are provided, either dependently upon the presence ofa sub-saturating concentration of an orthosteric agonist (such as theendogenous agonist glutamate) or independently. The method comprisescontacting mGluR5 in a cell or in a subject with an effective amount ofa potentiator, an allosteric agonist, or a positive allosteric modulatorIn some embodiments, the cell is a brain cell, such as, for example, aneuronal cell or a glial cell.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood by one of ordinaryskill in the art. All publications and patents referred to herein areincorporated by reference herein in their entirety.

As used herein, and unless otherwise indicated, the term “alkyl” refersto a linear or branched saturated monovalent hydrocarbon radical,wherein the alkyl may optionally be substituted with one or moresubstituents. In some embodiment, the alkyl may be optionallysubstituted with one or more halogen atoms. In certain embodiments, thealkyl is a linear saturated monovalent hydrocarbon radical that has 1 to20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 12 (C₁₋₁₂), 1 to 10 (C₁₋₁₀), or 1 to 6(C₁₋₆) carbon atoms, or branched saturated monovalent hydrocarbonradical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ andbranched C₃₋₆ alkyl groups are also referred as “lower alkyl.” Examplesof alkyl groups include, but are not limited to, methyl, ethyl, propyl(including all isomeric forms, such as n-propyl and isopropyl), butyl(including all isomeric forms such as n-butyl, isobutyl, and t-butyl),pentyl (including all isomeric forms), and hexyl (including all isomericforms). For example, C₁₋₆ alkyl refers to a linear saturated monovalenthydrocarbon radical of 1 to 6 carbon atoms or a branched saturatedmonovalent hydrocarbon radical of 3 to 6 carbon atoms. In someembodiments, alkyl includes, but is not limited to, heteroarylalkyl(heteroaralky) such as pyridylmethyl, cycloalkylalkyl such ascyclopropylmethyl, and heterocycloalkylalkyl such as pyrrolidinomethyl,each of which is optionally substituted.

The term “heteroalkyl” includes groups in which alkyl moieties, asdescribed above, are substituted with a heteroatom (e.g., O, N or S).One of skill in the art would be able to determine appropriateheteroalkyl moieties.

The term “bicyclic” as used herein includes fused, spirocylic, andbridged bicyclic compounds.

As used herein, and unless otherwise specified, the term “alkenyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbondouble bonds. The alkenyl may be optionally substituted with one or moresubstituents. In some embodiments, the alkenyl is optionally substitutedwith one or more halogen atoms. The term “alkenyl” also encompassesradicals having “cis” and “trans” configurations, or alternatively, “E”and “Z” configurations, as appreciated by those of ordinary skill in theart. As used herein, linear C₂₋₆ and branched C₃₋₆ alkenyl groups arealso referred as “lower alkenyl.” For example, C₂₋₆ alkenyl refers to alinear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atomsor a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12(C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branchedmonovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples ofalkenyl groups include, but are not limited to, ethenyl, propen-1-yl,propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

As used herein, and unless otherwise specified, the term “alkynyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbontriple bonds. The alkynyl may be optionally substituted with one or moresubstituents. In some embodiments, the alkynyl is optionally substitutedwith one or more halogen atoms. In certain embodiments, the alkynyl is alinear monovalent hydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15(C₂₋₁₅), 2 to 12 (C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbonatoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀),3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆)carbon atoms. Examples of alkynyl groups include, but are not limitedto, ethynyl (—C≡CH) and propargyl (—CH₂C≡CH). For example, C₂₋₆ alkynylrefers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6carbon atoms or a branched unsaturated monovalent hydrocarbon radical of3 to 6 carbon atoms.

As used herein, and unless otherwise specified, the terms “cycloalkyl,”“carbocycle” or “carbocyclic” refer to a cyclic saturated or partiallyunsaturated bridged and/or non-bridged monovalent hydrocarbon radical,which may be optionally substituted with one or more substituents asdescribed herein elsewhere. In certain embodiments, the cycloalkyl hasfrom 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 12 (C₃₋₁₂), from 3to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms. Examples ofcycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclopentenyl, cyclohexenyl, decalinyl, and adamantyl.

The term “alkylcycloalkyl” includes groups in which cycloalkyl moietiesare substituted with alkyl groups. One of skill in the art would be ableto determine appropriate alkylcycloalkyl moieties.

As used herein, and unless otherwise specified, the term “aryl” refersto a monocyclic aromatic group and/or multicyclic monovalent aromaticgroup that contain at least one aromatic hydrocarbon ring. In certainembodiments, the aryl has from 6 to 20 (C₆₋₂₀), from 6 to 15 (C₆₋₁₅), orfrom 6 to 10 (C₆₋₁₀) ring atoms. Examples of aryl groups include, butare not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl,phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to, forexample, bicyclic or tricyclic carbon rings, where at least one of therings is aromatic and the others of which may be saturated, partiallyunsaturated, or aromatic, for example, dihydronaphthyl, indenyl,indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments,aryl may also be optionally substituted with one or more substituents asdescribed herein.

As used herein, and unless otherwise specified, the term “arylalkyl” or“aralkyl” refers to a monovalent alkyl group substituted with aryl, suchas phenylmethyl (benzyl). In certain embodiments, both alkyl and arylare optionally substituted with one or more substituents as describedherein.

As used herein, the term “alkylaryl” includes an aryl moiety substitutedwith an alkyl group, such as methylphenyl (tolyl). One of skill in theart would be able to determine appropriate alkylaryl moieties.

As used herein, and unless otherwise specified, the term “heteroaryl”refers to a monocyclic aromatic group and/or multicyclic aromatic groupthat contain at least one aromatic ring, wherein at least one aromaticring contains one or more heteroatoms independently selected from O, S,and N. Each ring of a heteroaryl group can contain one or two O atoms,one or two S atoms, and/or one to four N atoms, provided that the totalnumber of heteroatoms in each ring is four or less and each ringcontains at least one carbon atom. In certain embodiments, theheteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.Examples of monocyclic heteroaryl groups include, but are not limitedto, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl,pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, andtriazolyl. Examples of bicyclic heteroaryl groups include, but are notlimited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl,benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl,benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl,imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl,isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl,pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl,thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclicheteroaryl groups include, but are not limited to, acridinyl,benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl,phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl,phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl isoptionally substituted with one or more substituents as describedherein.

The term “alkylheteroaryl” includes groups in which a heteroaryl moietyis substituted with an alkyl group. One of skill in the art would beable to determine appropriate alkylheteroalkyl moieties.

As used herein, and unless otherwise specified, the terms“heterocyclyl,” “heterocyclic” or “heterocycloalkyl” refer to amonocyclic non-aromatic ring system and/or multicyclic ring system thatcontains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, or N; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl or heterocyclic group has from 3 to 20,from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. In certain embodiments, the heterocyclyl is a monocyclic,bicyclic, tricyclic, or tetracyclic ring system, which may include afused or bridged ring system, and in which the nitrogen or sulfur atomsmay be optionally oxidized, the nitrogen atoms may be optionallyquaternized, and some rings may be partially or fully saturated, oraromatic. The heterocyclyl may be attached to the main structure at anyheteroatom or carbon atom which results in the creation of a stablecompound. Examples of such heterocyclic radicals include, but are notlimited to, azepinyl, azcanyl, azepanyl, azetidinyl, benzodioxanyl,benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl,benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl,benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl,coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,dihydrofuryl, dihydrobenzisoxazinyl, dihydroisoindolyl, dihydropyranyl,dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl,furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, oxetanyl, octahydroindolyl, octahydroisoindolyl,oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl,4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl,tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments,heterocyclyl or heterocyclic is optionally substituted with one or moresubstituents as described herein.

The term “alkylheterocycloalkyl” includes groups in which a heterocyclicmoiety is substituted with an alkyl group. One of skill in the art wouldbe able to determine appropriate alkylheterocycloalkyl moieties.

As used herein, and unless otherwise specified, the term “halogen”,“halide” or “halo” refers to fluorine, chlorine, bromine, and/or iodine.

As used herein, and unless otherwise specified, the term “optionallysubstituted” refers to a group, such as an alkyl, alkenyl, alkynyl,cycloalkyl, aryl, aralkyl, heteroaryl, heteroalkyl, alkylcycloalkyl,aralkyl, heteroaralkyl, alkylaryl, alkylheteroaryl, cycloalkyl,alkylheterocycloalkyl, or heterocyclyl, which may be substituted withone or more substituents independently selected from, e.g., (a) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsM¹; and (b) oxime (═N—OH), oxo (C═O), halo, cyano (—CN), nitro (—NO₂),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(e),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,each optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents M¹; or (iii) R^(b) and R^(e) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents M¹. As used herein,and unless otherwise specified, all groups that can be substituted are“optionally substituted.”

In one embodiment, each M¹ is independently selected from the groupconsisting of (a) cyano, halo, and nitro; and (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/stereomerically pure andenantiomerically/stereomerically enriched compounds set forth herein.

As used herein and unless otherwise specified, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stereoisomers of the compound,greater than about 97% by weight of one stereoisomer of the compound andless than about 3% by weight of the other stereoisomers of the compound,or greater than about 99% by weight of one stereoisomer of the compoundand less than about 1% by weight of the other stereoisomers of thecompound. In some embodiments, a compound may be greater than 99.5%,greater than 99.7%, or even greater than 99.9% by weight of onestereoisomer.

As used herein and unless otherwise specified, the term “stereomericallyenriched” means a composition that comprises greater than about 55% byweight of one stereoisomer of a compound, greater than about 60% byweight of one stereoisomer of a compound, greater than about 70% byweight, or greater than about 80% by weight of one stereoisomer of acompound.

As used herein, and unless otherwise specified, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center. Similarly, the term “enantiomericallyenriched” means a stereomerically enriched composition of a compoundhaving one chiral center.

As used herein, and unless otherwise specified, the term “opticallyactive” or “enantiomerically active” refers to a collection ofmolecules, which has an enantiomeric excess of no less than about 50%,no less than about 70%, no less than about 80%, no less than about 90%,no less than about 91%, no less than about 92%, no less than about 93%,no less than about 94%, no less than about 95%, no less than about 96%,no less than about 97%, no less than about 98%, no less than about 99%,no less than about 99.5%, or no less than about 99.8%. In certainembodiments, the compound comprises about 95% or more of the desiredenantiomer and about 5% or less of the less preferred enantiomer basedon the total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids. Suitable non-toxic acids include inorganic andorganic acids such as, but not limited to, acetic, alginic, anthranilic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,formic, fumaric, furoic, gluconic, glutamic, glucorenic, galacturonic,glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phenylacetic, propionic, phosphoric, salicylic, stearic, succinic,sulfanilic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Insome embodiments, the salt is formed from hydrochloric, hydrobromic,phosphoric, or sulfuric acid. In one embodiment, the salt is formed fromhydrochloride salt.

As used herein, and unless otherwise specified, the term “solvate”refers to a compound set forth herein or a salt thereof, which furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. For example,hydrogens represented by “H” in the formulae herein are intended torepresent all isotopic forms of hydrogen (e.g., ¹H, ²H or D, or ³H);carbons represented by “C” in the formulae herein are intended torepresent all isotopic forms of carbon (e.g., ¹¹C, ¹³C, or ¹⁴C);nitrogens represented by “N” are intended to represent all isotopicforms of nitrogen (e.g., ¹⁴N or ¹⁸N).

Other examples of isotopes that are included in the invention includeisotopes of oxygen, sulfur, phosphorous, fluorine, iodine and chlorine,such as ¹⁸F ³¹P, ³²P, ³⁵S, ¹⁵O ³⁶Cl and ¹²⁵1. The invention includesvarious isotopically labeled compounds as defined herein, for examplethose into which radioactive isotopes, such as ³H, ¹³C and ¹⁴C arepresent. In some embodiments, the atoms in the formulae herein occur intheir natural abundance. In some embodiments, one or more hydrogen atommay be enriched in ²H; or/and one or more carbon atom may be enriched in¹¹C ¹³C ¹⁴C; or/and one or more nitrogen may be enriched in ¹⁴N. Suchisotopically labeled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H). detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F or labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically labeled compounds ofthis invention and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the schemes or in the examplesand preparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

Further, enrichment with heavier isotopes, particularly deuterium (i.e.,²H or D) may afford certain therapeutic advantages resulting from, forexample, greater metabolic stability, such as increased in vivohalf-life or reduced dosage requirements or an improvement intherapeutic index. It is understood that deuterium in this context isregarded as a substituent of a compound as disclosed herein. Theconcentration of such a heavier isotopes, specifically deuterium, may bedefined by the isotopic enrichment factor. The term “isotopic enrichmentfactor” includes the ratio between the isotopic abundance and thenatural abundance of a specified isotope, if a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).Isotopically-enriched compounds as disclosed herein can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesusing an appropriate isotopically-enriched reagent in place of thenon-enriched reagent previously employed.

The compounds as disclosed herein may exhibit the phenomenon oftautomerism. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons. While the formulae cannot expressly depict allpossible tautomeric forms, it is to be understood that the compounds asdisclosed herein are intended to represent any tautomeric form of thedepicted compounds and are not to be limited merely to a specificcompound form depicted by the formula drawings. One of skill in the artby no more than routine experimentation would be able to determine whichcompounds may form tautomers and how to identify such tautomeric forms.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable carrier,” “pharmaceutically acceptableexcipient,” “physiologically acceptable carrier,” or “physiologicallyacceptable excipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. In one embodiment, each component is“pharmaceutically acceptable” in the sense of being compatible with theother ingredients of a pharmaceutical formulation, and suitable for usein contact with the tissue or organ of humans and animals withoutexcessive toxicity, irritation, allergic response, immunogenicity, orother problems or complications, commensurate with a reasonablebenefit/risk ratio. See, Remington: The Science and Practice ofPharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia,Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe etal., Eds., The Pharmaceutical Press and the American PharmaceuticalAssociation: 2005; and Handbook of Pharmaceutical Additives, 3rdEdition, Ash and Ash Eds., Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed.,CRC Press LLC: Boca Raton, Fla., 2009.

As used herein, and unless otherwise specified, the term “about” or“approximately” means an acceptable error for a particular value asdetermined by one of ordinary skill in the art, which depends in part onhow the value is measured or determined. In certain embodiments, theterm “about” or “approximately” means within 1, 2, 3, or 4 standarddeviations. In certain embodiments, the term “about” or “approximately”means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,0.5%, or 0.05% of a given value or range.

As used herein, and unless otherwise specified, the terms “activeingredient” and “active substance” refer to a compound, which isadministered, alone or in combination with one or more pharmaceuticallyacceptable excipients, to a subject for treating, preventing, orameliorating one or more symptoms of a condition, disorder, or disease.As used herein, “active ingredient” and “active substance” may be anoptically active isomer of a compound described herein. In someembodiments, the active ingredient is a compound as disclosed herein.

As used herein, and unless otherwise specified, the terms “drug,”“therapeutic agent,” and “chemotherapeutic agent” refer to a compound,or a pharmaceutical composition thereof, which is administered to asubject for treating, preventing, or ameliorating one or more symptomsof a condition, disorder, or disease (e.g., a disease or disorderrelated to mGluR5). In some embodiments, the therapeutic agent is acompound as disclosed herein.

As used herein, and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder (e.g., a disease or disorder related to mGluR5). Incertain embodiments, the terms refer to minimizing the spread orworsening of the disease or disorder resulting from the administrationof one or more therapeutic agents to a subject with such a disease ordisorder. In some embodiments, the terms refer to the administration ofa compound as disclosed herein, a mixture thereof (with or without otheradditional active agent(s)), a solvate (e.g., hydrate), a prodrug or apharmaceutically acceptable salt of either, after the onset of symptomsof the particular disease.

As used herein, and unless otherwise indicated, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or transmission of a disease or disorder, or of one or moresymptoms thereof (e.g., a disease or disorder related to mGluR5). Incertain embodiments, the terms refer to the treatment with oradministration of a compound as disclosed herein, a mixture thereof(with or without other additional active agent(s)), a solvate (e.g.,hydrate), a prodrug or a pharmaceutically acceptable salt of either,prior to the onset of symptoms, particularly to patients at risk ofdisease or disorders provided herein. The terms encompass the inhibitionor reduction of a symptom of the particular disease. Patients withfamilial history of a disease in particular are candidates forpreventive regimens in certain embodiments. In addition, patients whohave a history of recurring symptoms are also potential candidates forthe prevention. In this regard, the term “prevention” may beinterchangeably used with the term “prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing,” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof (e.g., a disease or disorder related to mGluR5).In some embodiments, the terms refer to management with a compound asdisclosed herein. Often, the beneficial effects that a subject derivesfrom a prophylactic and/or therapeutic agent do not result in a cure ofthe disease or disorder. In this regard, the term “managing” encompassestreating a patient who had suffered from the particular disease in anattempt to prevent or minimize the recurrence of the disease.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder (e.g., a disease or disorder related to mGluR5).A therapeutically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other therapies, whichprovides a therapeutic benefit in the treatment or management of thedisease or disorder. The term “therapeutically effective amount” canencompass an amount that improves overall therapy, reduces or avoidssymptoms or causes of disease or disorder, or enhances the therapeuticefficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence (e.g., a disease ordisorder related to mGluR5). A prophylactically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other agents, which provides a prophylactic benefit in theprevention of the disease. The term “prophylactically effective amount”can encompass an amount that improves overall prophylaxis or enhancesthe prophylactic efficacy of another prophylactic agent.

As used herein, and unless otherwise specified, the term “subject” isdefined herein to include animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In some embodiments, the subjectis a human. In some embodiments, the subject is suffering from a diseaseor disorder related to mGluR5. In some embodiments, the subject is atrisk of suffering from a disease or disorder related to mGluR5.

As used herein, and unless otherwise specified, the term “metabotropicglutamate receptor ligand” or “mGluR ligand” refers to any compound,which binds to an mGluR receptor. Unless otherwise specified, the mGluRreceptor includes, but is not limited to mGluR5. Ligands includeendogenous ligands for a given metabotropic glutamate receptor as wellas drug molecules and other compounds, such as synthetic molecules knownto bind to a particular metabotropic glutamate receptor. In someembodiments, the ligand is an allosteric modulator (e.g., a positive ornegative allosteric modulator). In some embodiments, the ligand is anmGluR5 agonist. In some embodiments the ligand is an mGluR5 antagonist.In one embodiment, the ligands include those labeled with one or moreradioisotopes, such as tritium or ¹¹C, or otherwise (e.g.,fluorescently) labeled. In some embodiments, the ligand is apositron-emission tomography (PET) ligand. It is within the abilities ofthe skilled person to select an appropriate ligand, for example, anagonist or an antagonist, for a given metabotropic glutamate receptor.

As used herein, mGluR5 modulator is a modulator that regulates theactivity of the mGluR5 receptor. An mGluR5 modulator can be a positivemodulator, which increases the activity of mGluR5 receptor. An mGluR5modulator may also be a negative modulator, which decreases the activityof the mGluR5 receptor. An mGluR5 modulator used herein may be anallosteric modulator. Such an allosteric modulator can be a positiveallosteric modulator or a negative allosteric modulator.

As used herein, and unless otherwise specified, the terms “diseases” and“disorders” are used interchangeably.

Neurological Diseases and Disorders

As used herein, and unless otherwise specified, the term “neurologicaldisorder” includes diseases, disorders or conditions of the central orperipheral nervous system of a mammal. The term “neurological disorder”includes, but is not limited to, neurodegenerative diseases,neuropsychiatric diseases, affective disorders, and loss of cognitivefunction, learning and memory disorders. The term “neurologicaldisorder” also includes conditions associated with the disorder. Forinstance, a method of treating a neurodegenerative disorder includesmethods of treating loss of memory and/or loss of cognition associatedwith a neurodegenerative disorder. The term “neurological disorder” alsoincludes diseases or conditions that are implicated, at least in part,in monoamine (e.g., norepinephrine) signaling pathways (e.g.,cardiovascular disease).

Neurodegenerative Diseases and Disorders

The term “neurodegenerative disease” includes diseases and disordersthat are associated with the progressive loss of structure or functionof neurons, or death of neurons. Neurodegenerative diseases anddisorders include, but are not limited to, Alzheimer's disease(including the associated symptoms of mild, moderate, or severecognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic andischemic injuries; ataxia and convulsion (including for the treatmentand prevention and prevention of seizures that are caused byschizoaffective disorder or by drugs used to treat schizophrenia);benign forgetfulness; brain edema; cerebellar ataxia including McLeodneuroacanthocytosis syndrome (MLS); closed head injury; coma; contusiveinjuries (e.g., spinal cord injury and head injury); dementias includingmulti-infarct dementia and senile dementia; disturbances ofconsciousness; Down syndrome; drug-induced or medication-inducedParkinsonism (such as neuroleptic-induced acute akathisia, acutedystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignantsyndrome, or medication-induced postural tremor); epilepsy; fragile Xsyndrome; Gilles de la Tourette's syndrome; head trauma; hearingimpairment and loss; Huntington's disease; Lennox syndrome;levodopa-induced dyskinesia; mental retardation; movement disordersincluding akinesias and akinetic (rigid) syndromes (including basalganglia calcification, corticobasal degeneration, multiple systematrophy, parkinsonism-ALS dementia complex, Parkinson's disease,postencephalitic parkinsonism, and progressively supranuclear palsy);muscular spasms and disorders associated with muscular spasticity orweakness including chorea (such as benign hereditary chorea,drug-induced chorea, hemiballism, Huntington's disease,neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea),dyskinesia (including tics such as complex tics, simple tics, andsymptomatic tics), myoclonus (including generalized myoclonus and focalcyloclonus), tremor (such as rest tremor, postural tremor, and intentiontremor) and dystonia (including axial dystonia, dystonic writer's cramp,hemiplegic dystonia, paroxymal dystonia, and focal dystonia such asblepharospasm, oromandibular dystonia, and spasmodic dysphonia andtorticollis); neuronal damage including ocular damage, retinopathy ormacular degeneration of the eye; neurotoxic injury which followscerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebralischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia,perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure;status epilecticus; stroke; tinnitus; and viral infection inducedneurodegeneration (e.g., caused by acquired immunodeficiency syndrome(AIDS) and encephalopathies). Neurodegenerative diseases also include,but are not limited to, neurotoxic injury which follows cerebral stroke,thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebralvasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxiaand cardiac arrest. Methods of treating or preventing aneurodegenerative disease also include treating or preventing loss ofneuronal function characteristic of neurodegenerative disorder.

Neuropsychiatric Diseases and Disorders

The term “neuropsychiatric disease” includes those neuropsychiatricdiseases and disorders set forth in The Diagnostic and StatisticalManual of Mental Disorders, Revised, Fourth Ed., (DSM-IV-R), publishedby the American Psychiatric Association, which is incorporated herein byreference. Such disorders include, but are not limited to, aggression;attention disorders including attention-deficit disorder (ADD),attention-deficit-hyperactivity disorder (ADHD) and conduct disorder;delirium; delusional disorder; persisting dementia; pervasivedevelopment disorder including autism, autistic disorder and autismspectrum disorder; psychosis and psychotic disorders (includingpsychosis associated with affective disorders, brief reactive psychosis,brief psychotic disorder, shared psychotic disorder, and psychoticdisorder due to a general medical condition and substance-induced ordrug-induced psychotic disorder (e.g., caused by phencyclidine, ketamineand other dissociative anaesthetics, amphetamine, cocaine and otherpsychostimulants)); schizophrenia (including schizoaffective psychosisand “schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, or illnesses associated with psychosis (such asmajor depression, manic depressive (bipolar) disorder, Alzheimer'sdisease and post-traumatic stress syndrome) including both the positiveand negative symptoms of schizophrenia and other psychoses); and sensoryhyper-excitability.

The terms “attention deficit disorder” (ADD), “attention deficitdisorder with hyperactivity (ADDH),” and “attentiondeficit/hyperactivity disorder” (AD/HD), are used herein in accordancewith the accepted meanings as found in the Diagnostic and StatisticalManual of Mental Disorders, 4th Ed., American Psychiatric Association(DSM-IV™-R). ADD and ADHD include disorders that are most prevalent inchildren and are associated with increased motor activity and adecreased attention span that may result in inappropriate actions inlearning and social situations.

The term “psychosis” includes mental states in which a subject sufferingfrom psychosis undergoes a loss of contact with reality. Symptoms ofpyschosis include hallucinations, delusions and impaired sight. In someembodiments, the psychosis may be associated with anotherneuropsychiatric disorder, for example, schizophrenia, schizophreniformdisorder, schizoaffective disorder, brief psychotic disorder, bipolardisorder, clinical depression, psychosocial disorder. In someembodiments, the psychosis is related to general medical conditions, forexample, brain tumors, brain damage, an epileptic disorder, dementia,multiple sclerosis, Lyme disease, Alzheimer's disease, Parkinson'sdisease, electrolyte disorders, hypoglycemia and AIDS. In someembodiments, the psychosis is substance-induced psychosis.

The term “schizophrenia” includes a mental disorders characterized bythe disintegration of the process of thinking and emotionalresponsiveness, and includes symptoms such as auditory hallucinations,paranoid delusions, disorganized speech, disorganized thinking, andextensive withdrawal of the patient's interests from other people. Theterm “schizophrenia” also includes schizophreniform disorder andschizoaffective disorder. So-called negative symptoms of schizophreniainclude affect blunting, anergia, alogia and social withdrawal. Positivesymptoms of schizophrenia include delusion and hallucination. Cognitivesymptoms of schizophrenia include impairment in obtaining, organizing,and using intellectual knowledge.

Affective Disorders

As used herein, and unless otherwise specified, the term “affectivedisorder” includes agoraphobia; anxiety and anxiety disorders (includingbut not limited to acute stress disorder, anxiety due to a generalmedical condition, dental phobia, generalized anxiety disorder, panicdisorder, separation anxiety disorder, social anxiety disorder, socialphobia, specific phobia, and substance-induced anxiety disorder);bipolar disorders; depression (including but not limited to dysthymia,major depressive disorder, seasonal affective disorder, seasonaldepression, unipolar depression, and post-partum depression); fatigueassociated with depression including but limited to chronic fatiguesyndrome; mood disorders (including disorders due to a general medicalcondition and substance-induced mood-disorders); obsessive-compulsivedisorder; panic attack; perimenopause, menopause, and male menopause;post-traumatic stress disorder; premenstrual syndrome (PMS) andpremenstrual dysphoric disorder (PDD); and sleep disorders includinginsomnia and narcolepsy.

Cognitive Function, Learning, and Memory Disorders

As used herein, and unless otherwise specified, the terms “cognitivedysfunction,” “cognitive function disorder,” “learning disorder”, and“memory disorder” apply to disorders that may be treated by improvingmammalian brain function. The terms include disorders in which subjectsexhibit symptoms of memory or learning loss, have impaired ability tolearn new information or to recall previously learned information orpast efforts. In some embodiments, these disorders cause markedimpairment in social or occupational functioning and represent asignificant decline from a previous level of functions. In someembodiments, the cognitive dysfunction may be associated with, forexample, adult and childhood learning disorders; altruism; amnesticdisorders (including Alzheimer's disease-related cognitive decline,normal age-related cognitive decline and persisting amnestic disorder);associative learning; attention; benign forgetfulness; cognitivedeficits induced by situational stress (including but not limited tooperating machinery for extended time periods or working in emergency orcombat situations); cognitive disorders including dementia (associatedwith acquired immunodeficiency disease, Alzheimer's disease,Creutzfeldt-Jacob disease, HIV infection, Huntington's disease,ischemia, multi-infarct dementia, Parkinson's disease, perinatalhypoxia, Pick's disease, trauma, vascular problems or stroke, othergeneral medical conditions or substance abuse); cooperativity;declarative memory; early consolidation; empathy; episodic memory;executive function; explicit memory; implicit memory; imprinting;language; late consolidation; learning (including electronic, formal,informal, multimedia and rote learning); low IQ; memory deficit; memoryloss; mild cognitive impairment (MCI); non-verbal and verbalcommunicative skills; play; rehearsal; retrieval, semantic memory;sensory integration of environmental cues including temperature, odor,sounds, touch, and taste; social cognition; and speech disorders.

Substance Abuse and Eating Disorders

The term “substance abuse” includes a pattern of behavior in which asubject uses a substance in a abusive manner and is used herein in amanner consistent with its accepted meaning in the art. (See, e.g.,DSM-IV™.) Examples of substance abuse include abuse of or addiction tocanabbis, cocaine, morphine, opioids, nicotine, or alcohol;substance-abuse related disorders and addictive behaviors (includingsubstance-induced delirium); tolerance, dependence or withdrawal fromsubstances including alcohol, amphetamines, anxiolytics, cannabis,cocaine, hallucinogens, hypnotics, inhalants, nicotine, opioids,phencyclidine, or sedatives.

The term “eating disorder,” as used herein, refers to abnormalcompulsions to avoid eating or uncontrollable impulses to consumeabnormally large amounts of food. Eating disorders include, but are notlimited to, anorexia nervosa, binge eating, bulimia nervosa, cachexia,compulsive eating disorder, emesis, and obesity.

Pain

As used herein, and unless otherwise specified, the term “pain” refersto an unpleasant sensory and emotional experience. The term “pain,” asused herein, refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, carpal tunnel syndrome, AIDS pain, arthropathy, migraine,trigeminal neuralgia, cardiac ischaemia, neuropathy arising from chronicalcohol use, and diabetic peripheral neuropathic pain (see, e.g.,Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al.,eds., 12th ed. 1991); Williams et al., J. of Med. Chem. 42: 1481-1485(1999), herein each incorporated by reference in their entirety). “Pain”is also meant to include mixed etiology pain, dual mechanism pain,allodynia, causalgia, central pain, hyperesthesia, hyperpathia,dysesthesia, and hyperalgesia. In addition, the term “pain” includespain resulting from dysfunction of the nervous system: organic painstates that share clinical features of neuropathic pain and possiblecommon pathophysiology mechanisms, but are not initiated by anidentifiable lesion in any part of the nervous system.

The term “somatic pain,” as used herein, refers to a normal nerveresponse to a noxious stimulus such as injury or illness, e.g., trauma,burn, infection, inflammation, or disease process such as cancer, andincludes both cutaneous pain (e.g., skin, muscle or joint derived) andvisceral pain (e.g., organ derived).

The term “neuropathic pain,” as used herein, refers to a heterogeneousgroup of neurological conditions that result from damage to the nervoussystem. The term also refers to pain resulting from injury to ordysfunctions of peripheral and/or central sensory pathways, and fromdysfunctions of the nervous system, where the pain often occurs orpersists without an obvious noxious input. This includes pain related toperipheral neuropathies as well as central neuropathic pain. Commontypes of peripheral neuropathic pain include diabetic neuropathy (alsocalled diabetic peripheral neuropathic pain, or DN, DPN, or DPNP),post-herpetic neuralgia (PHN), and trigeminal neuralgia (TGN). Centralneuropathic pain, involving damage to the brain or spinal cord, canoccur following stroke, spinal cord injury, and as a result of multiplesclerosis, and is also encompassed by the term. Other types of pain thatare meant to be included in the definition of neuropathic pain include,but are not limited to, pain from neuropathic cancer pain, HIV/AIDSinduced pain, phantom limb pain, and complex regional pain syndrome.

The term also encompasses the common clinical features of neuropathicpain including, but not limited to, sensory loss, allodynia (non-noxiousstimuli produce pain), hyperalgesia and hyperpathia (delayed perception,summation, and painful after sensation). Pain is often a combination ofnociceptive and neuropathic types, for example, mechanical spinal painand radiculopathy or myelopathy.

As used herein, and unless otherwise specified, the term “acute pain”refers to the normal, predicted physiological response to a noxiouschemical, thermal or mechanical stimulus typically associated withinvasive procedures, trauma and disease. It is generally time-limited,and may be viewed as an appropriate response to a stimulus thatthreatens and/or produces tissue injury. The term also refers to painwhich is marked by short duration or sudden onset.

As used herein, and unless otherwise specified, the term “chronic pain”encompasses the pain occurring in a wide range of disorders, forexample, trauma, malignancies and chronic inflammatory diseases such asrheumatoid arthritis. Chronic pain may last more than about six months.In addition, the intensity of chronic pain may be disproportionate tothe intensity of the noxious stimulus or underlying process. The termalso refers to pain associated with a chronic disorder, or pain thatpersists beyond resolution of an underlying disorder or healing of aninjury, and that is often more intense than the underlying process wouldpredict. It may be subject to frequent recurrence.

As used herein, and unless otherwise specified, the term “inflammatorypain” is pain in response to tissue injury and the resultinginflammatory process. Inflammatory pain is adaptive in that it elicitsphysiologic responses that promote healing. However, inflammation mayalso affect neuronal function. Inflammatory mediators, including PGE2induced by the COX2 enzyme, bradykinins, and other substances, bind toreceptors on pain-transmitting neurons and alter their function,increasing their excitability and thus increasing pain sensation. Muchchronic pain has an inflammatory component. The term also refers to painwhich is produced as a symptom or a result of inflammation or an immunesystem disorder.

As used herein, and unless otherwise specified, the term “visceral pain”refers to pain which is located in an internal organ.

As used herein, and unless otherwise specified, the term “mixed etiologypain” refers to pain that contains both inflammatory and neuropathiccomponents.

As used herein, and unless otherwise specified, the term “dual mechanismpain” refers to pain that is amplified and maintained by both peripheraland central sensitization.

As used herein, and unless otherwise specified, the term “causalgia”refers to a syndrome of sustained burning, allodynia, and hyperpathiaafter a traumatic nerve lesion, often combined with vasomotor andsudomotor dysfunction and later trophic changes.

As used herein, and unless otherwise specified, the term “central pain”refers to pain initiated by a primary lesion or dysfunction in thecentral nervous system.

As used herein, and unless otherwise specified, the term “hyperesthesia”refers to increased sensitivity to stimulation, excluding the specialsenses.

As used herein, and unless otherwise specified, the term “hyperpathia”refers to a painful syndrome characterized by an abnormally painfulreaction to a stimulus, especially a repetitive stimulus, as well as anincreased threshold. It may occur with allodynia, hyperesthesia,hyperalgesia, or dysesthesia.

As used herein, and unless otherwise specified, the term “dysesthesia”refers to an unpleasant abnormal sensation, whether spontaneous orevoked. In certain embodiments, dysesthesia include hyperalgesia andallodynia.

As used herein, and unless otherwise specified, the term “hyperalgesia”refers to an increased response to a stimulus that is normally painful.It reflects increased pain on suprathreshold stimulation.

As used herein, and unless otherwise specified, the term “allodynia”refers to pain due to a stimulus that does not normally provoke pain.

As used herein, and unless otherwise specified, the term “DiabeticPeripheral Neuropathic Pain” (DPNP), also called diabetic neuropathy, DNor diabetic peripheral neuropathy), refers to chronic pain caused byneuropathy associated with diabetes mellitus. The classic presentationof DPNP is pain or tingling in the feet that can be described not onlyas “burning” or “shooting” but also as severe aching pain. Lesscommonly, patients may describe the pain as itching, tearing, or like atoothache. The pain may be accompanied by allodynia and hyperalgesia andan absence of symptoms, such as numbness.

As used herein, and unless otherwise specified, the term “Post-HerpeticNeuralgia”, also called “Postherpetic Neuralgia (PHN)”, refers to apainful condition affecting nerve fibers and skin. Without being limitedby a particular theory, it is a complication of shingles, a secondoutbreak of the varicella zoster virus (VZV), which initially causeschickenpox.

As used herein, and unless otherwise specified, the term “neuropathiccancer pain” refers to peripheral neuropathic pain as a result ofcancer, and can be caused directly by infiltration or compression of anerve by a tumor, or indirectly by cancer treatments such as radiationtherapy and chemotherapy (chemotherapy-induced neuropathy).

As used herein, and unless otherwise specified, the term “HIV/AIDSperipheral neuropathy” or “HIV/AIDS related neuropathy” refers toperipheral neuropathy caused by HIV/AIDS, such as acute or chronicinflammatory demyelinating neuropathy (AIDP and CIDP, respectively), aswell as peripheral neuropathy resulting as a side effect of drugs usedto treat HIV/AIDS.

As used herein, and unless otherwise specified, the term “Phantom LimbPain” refers to pain appearing to come from where an amputated limb usedto be. Phantom limb pain can also occur in limbs following paralysis(e.g., following spinal cord injury). “Phantom Limb Pain” is usuallychronic in nature.

As used herein, and unless otherwise specified, the term “TrigeminalNeuralgia (TN)” refers to a disorder of the fifth cranial (trigeminal)nerve that causes episodes of intense, stabbing, electric-shock-likepain in the areas of the face where the branches of the nerve aredistributed (lips, eyes, nose, scalp, forehead, upper jaw, and lowerjaw). It is also known as the “suicide disease”.

As used herein, and unless otherwise specified, the term “ComplexRegional Pain Syndrome (CRPS),” formerly known as Reflex SympatheticDystrophy (RSD), refers to a chronic pain condition whose key symptom iscontinuous, intense pain out of proportion to the severity of theinjury, which gets worse rather than better over time. The termencompasses type 1 CRPS, which includes conditions caused by tissueinjury other than peripheral nerve, and type 2 CRPS, in which thesyndrome is provoked by major nerve injury, and is sometimes calledcausalgia.

As used herein, and unless otherwise specified, the term “fibromyalgia”refers to a chronic condition characterized by diffuse or specificmuscle, joint, or bone pain, along with fatigue and a range of othersymptoms. Previously, fibromyalgia was known by other names such asfibrositis, chronic muscle pain syndrome, psychogenic rheumatism andtension myalgias.

As used herein, and unless otherwise specified, the term “convulsion”refers to a neurological disorder and is used interchangeably with“seizure,” although there are many types of seizure, some of which havesubtle or mild symptoms instead of convulsions. Seizures of all typesmay be caused by disorganized and sudden electrical activity in thebrain. In some embodiments, convulsions are a rapid and uncontrollableshaking during which the muscles contract and relax repeatedly.

Compounds

In various embodiments, a compound of formula (I) is provided:

wherein.

R¹ is hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, arylor heteroaryl, each of which is optionally substituted;

R² is hydrogen, lower alkyl, lower alkenyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl,alkylheteroaryl, aryl, heteroaryl, —C(O)OR¹², or —CO—NR¹², each of whichis optionally substituted;

R³ is hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, arylor heteroaryl, each of which is optionally substituted; or

R² and R³ are optionally joined, together with the atoms to which theyare attached, to form a mono or bicyclic ring that is carbocyclic orheterocyclic, each of which is optionally substituted;

G is CHR² or NR² when b and c are both single bonds, or G is CR² or Nwhen one of b and c is a double bond;

Q is NH or CH₂ when d and e are single bonds, or N or CH when one of dor e is a double bond, or;

X is CH or N when f is a single bond, or C when f is a double bond;

Z is CH₂, C═O, C═S or a bond when b is a single bond, or CH or N when bis a double bond;

b, c, d, e, and f are each independently a single bond or a double bond,provided that when b is a double bond, c is a single bond; when c is adouble bond, b and d are single bonds; when d is a double bond, c and eare single bonds; when e is a double bond, d and f are single bonds; andwhen f is a double bond, e is a single bond;

Y¹, Y² and Y³ are each independently CH, C-halogen, C-lower alkyl, or N,provided that no more than one of Y² and Y³ is N;

L¹ is —C≡C—, —HC═CH—, -(lower alkyl)C═C(lower alkyl)-, —CH₂—CH₂—,—CO—CH₂—, —CH(OH)—CH₂, —CH₂—CO—, —C₀₋₆alkyl-O—C₀₋₆alkyl-, —NR¹²SO—,—SONR¹²—, —NR¹²SO₂—, —SO₂NR¹²—, —NR¹²—CO—, —CO—NR¹²—,

R¹² is hydrogen or lower alkyl;

W¹ and W² are each independently N or CH;

W³ is O, S or NR⁴; and

R⁴ is hydrogen or lower alkyl;

or a pharmaceutically acceptable salt thereof;

provided that at least one of c and d is a double bond.

In one embodiment, at least one of G, Q, and X is a nitrogen atom. Inone embodiment, at least two of G, Q, and X is a nitrogen atom. In oneembodiment, both Q and G are nitrogen atoms. In one embodiment, both Qand X are nitrogen atoms.

In one embodiment, at least one of d and e is a double bond.

In one embodiment, R¹ is hydrogen. In another embodiment, R¹ isoptionally substituted lower alkyl. In another embodiment, R¹ isoptionally substituted heteroalkyl. In another embodiment, R¹ isoptionally substituted cycloalkyl. In another embodiment, R¹ isoptionally substituted monocyclic cycloalkyl. In another embodiment, R¹is optionally substituted heterocycloalkyl. In another embodiment, R¹ isoptionally substituted monocyclic heterocycloalkyl. In anotherembodiment, R¹ is optionally substituted alkylcycloalkyl. In anotherembodiment, R¹ is optionally substituted monocyclic alkylcycloalkyl. Inanother embodiment, R¹ is optionally substituted alkylheterocycloalkyl.In another embodiment, R¹ is optionally substituted monocyclicalkylheterocycloalkyl. In another embodiment, R¹ is optionallysubstituted alkylaryl. In another embodiment, R¹ is optionallysubstituted monocyclic alkylaryl. In another embodiment, R¹ isoptionally substituted alkylheteroaryl. In another embodiment, R¹ isoptionally substituted monocyclic alkylheteroaryl. In anotherembodiment, R¹ is optionally substituted aryl. In another embodiment, R¹is optionally substituted monocyclic aryl. In another embodiment, R¹ isoptionally substituted heteroaryl. In another embodiment, R¹ isoptionally substituted monocyclic heteroaryl.

In one embodiment, R² is hydrogen, lower alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl,alkylheteroaryl, aryl, or heteroaryl, each of which is optionallysubstituted. In one embodiment, R² is hydrogen. In another embodiment,R² is optionally substituted lower alkyl. In another embodiment, R² isoptionally substituted heteroalkyl. In another embodiment, R² isoptionally substituted cycloalkyl. In another embodiment, R² isoptionally substituted monocyclic cycloalkyl. In another embodiment, R²is optionally substituted heterocycloalkyl. In another embodiment, R² isoptionally substituted monocyclic heterocycloalkyl. In anotherembodiment, R² is optionally substituted alkylcycloalkyl. In anotherembodiment, R² is optionally substituted monocyclic alkylcycloalkyl. Inanother embodiment, R² is optionally substituted alkylheterocycloalkyl.In another embodiment, R² is optionally substituted monocyclicalkylheterocycloalkyl. In another embodiment, R² is optionallysubstituted alkylaryl. In another embodiment, R² is optionallysubstituted monocyclic alkylaryl. In another embodiment, R² isoptionally substituted alkylheteroaryl. In another embodiment, R² isoptionally substituted monocyclic alkylheteroaryl. In anotherembodiment, R² is optionally substituted aryl. In another embodiment, R²is optionally substituted monocyclic aryl. In another embodiment, R² isoptionally substituted heteroaryl. In another embodiment, R² isoptionally substituted monocyclic heteroaryl. In another embodiment R²is lower alkenyl. In another embodiment, R² is —C(O)OR¹². In anotherembodiment, R² is —CO—NR¹².

In one embodiment, R³ is hydrogen. In another embodiment, R³ isoptionally substituted lower alkyl. In another embodiment, R³ isoptionally substituted heteroalkyl. In another embodiment, R³ isoptionally substituted cycloalkyl. In another embodiment, R³ isoptionally substituted monocyclic cycloalkyl. In another embodiment, R³is optionally substituted heterocycloalkyl. In another embodiment, R³ isoptionally substituted monocyclic heterocycloalkyl. In anotherembodiment, R³ is optionally substituted alkylcycloalkyl. In anotherembodiment, R³ is optionally substituted monocyclic alkylcycloalkyl. Inanother embodiment, R³ is optionally substituted alkylheterocycloalkyl.In another embodiment, R³ is optionally substituted monocyclicalkylheterocycloalkyl. In another embodiment, R³ is optionallysubstituted alkylaryl. In another embodiment, R³ is optionallysubstituted monocyclic alkylaryl. In another embodiment, R³ isoptionally substituted alkylheteroaryl. In another embodiment, R³ isoptionally substituted monocyclic alkylheteroaryl. In anotherembodiment, R³ is optionally substituted aryl. In another embodiment, R³is optionally substituted monocyclic aryl. In another embodiment, R³ isoptionally substituted heteroaryl. In another embodiment, R³ isoptionally substituted monocyclic heteroaryl.

In another embodiment, R² and R³ are linked to form a 5- to 8-memberedmono or bicyclic ring that is carbocyclic or heterocyclic, any of whichis optionally substituted. In another embodiment, R² and R³ are linkedto form a mono or bicyclic ring that is carbocyclic or heterocyclic, anyof which is optionally substituted. In another embodiment, R² and R³ arelinked to form a monocyclic ring that is carbocyclic. In anotherembodiment, R² and R³ are linked to form a monocyclic ring that isheterocyclic. In another embodiment R² and R³ are linked to form abicyclic ring that is carbocyclic. In another embodiment R² and R³ arelinked to form a bicyclic ring that is heterocyclic.

In one embodiment, G is CHR², NR², or CR². In one embodiment, G is CR².In another embodiment, G is NR². In another embodiment, G is N. Inanother embodiment G is CHR².

In one embodiment, Q is N. In another embodiment, Q is CH. In oneembodiment, Q is NH. In one embodiment, Q is CH₂.

In one embodiment, X is C. In another embodiment, X is N. In anotherembodiment, X is CH.

In one embodiment, Z is C═O or a bond when b is a single bond, or CH orN when e is a double bond. In one embodiment, Z is CH₂. In anotherembodiment, Z is C═O. In another embodiment, Z is a bond. In anotherembodiment, Z is C═S.

In one embodiment, b is a single bond. In one embodiment, b is a doublebond and c is a single bond. In one embodiment, c is a single bond. Inone embodiment, c is a double bond, and b and d are single bonds. In oneembodiment, d is a single bond. In one embodiment, d is a double bond,and c and e are single bonds. In one embodiment, e is a single bond. Inone embodiment, e is a double bond, and d and f are single bonds. In oneembodiment, f is a single bond. In one embodiment, f is a double bondand e is a single bond

In one embodiment, Y¹ is CH. In another embodiment, Y¹ is CF. In anotherembodiment, Y¹ is N. In one embodiment Y¹ is C-halogen, such as C—F,C—Cl, C—Br, or C—I. In one embodiment, Y¹ is C-lower alkyl.

In one embodiment, Y² is CH. In another embodiment, Y² is CF. In anotherembodiment, Y² is N. In one embodiment Y² is C-halogen, such as C—F,C—Cl, C—Br, or C—I. In one embodiment, Y² is C-lower alkyl.

In one embodiment, Y³ is CH. In another embodiment, Y³ is CF. In anotherembodiment, Y³ is N. In one embodiment Y³ is C-halogen, such as C—F,C—Cl, C—Br, or C—I. In one embodiment, Y³ is C-lower alkyl.

In an exemplary embodiment according to the description above no morethan one of Y² and Y³ is N.

In one embodiment, L¹ is —C≡C—, —HC═CH—, —CH₂—CH₂—, —CO—CH₂—,—CH(OH)—CH₂, —CH₂—CO—, —NR¹²—CO—, —CO—NR¹²—,

In one embodiment, L¹ is —C≡C—. In another embodiment, L¹ is (loweralkyl)-C═C— (lower alkyl)-. In another embodiment, L¹ is —HC═CH—. Inanother embodiment, L¹ is —CH₂—CH₂—. In another embodiment, L¹ is—CO—CH₂—. In another embodiment, L¹ is —CH₂—CO—. In another embodiment,L¹ is —NR¹²—CO—. In another embodiment, L¹ is —CO—NR¹²—. In anotherembodiment, L¹ is C₀₋₆alkyl-O—C₀₋₆alkyl. In another embodiment, L¹ is—NR¹²SO—. In another embodiment, L¹ is —SONR¹²—. In another embodiment,L¹-NR¹²SO₂—. In another embodiment, L¹ is —SO₂NR¹²—. In anotherembodiment, L¹ is —C₀₋₆alkyl-O—C₀₋₆alkyl-. R¹² is defined hereinelsewhere.

In another embodiment, L¹ is:

In another embodiment, L¹ is:

In another embodiment, L¹ is:

In another embodiment, L¹ is:

In another embodiment, L¹ is:

In one embodiment, R¹² is hydrogen. In another embodiment, R¹² is loweralkyl.

In one embodiment, W¹ is N. In another embodiment, W¹ is CH.

In one embodiment, W² is N. In another embodiment, W² is CH.

In one embodiment, W³ is O. In another embodiment, W³ is S. In anotherembodiment, W³ is NR⁴. R⁴ is defined herein elsewhere.

In one embodiment, R⁴ is hydrogen. In another embodiment, R⁴ is loweralkyl.

Any of the combinations of R¹, R², R³, G, Q, X, Z, Y¹, Y², Y³, L¹, R¹²,W¹, W², W³, and R⁴ are encompassed by this disclosure and specificallyprovided by the invention.

In some aspects, the invention provides compounds of formula (Ia):

wherein

R^(1a) is aryl, heteroaryl or cycloalkyl, each of which is optionallysubstituted;

L^(1a) is —C≡C—, —HC═CH—, —CH₂CH₂—, —C(O)NH—, —NHC(O)—, CH(OH)CH₂—,C(O)CH₂,

Y^(1a), Y^(2a) and Y^(3a) are each independently CH, N, or C-halogen,provided that no more than one of Y^(2a) and Y^(3a) is N;

c, d e, and f are each independently single or double bonds; providedthat when c is a double bond, d is a single bond; when d is a doublebond, c and e are single bonds; when e is a double bond, d and f aresingle bonds; and when f is a double bond, e is a single bond;

X^(a) is N when f is a single bond or C when f is a double bond;

Q^(a) is NH when d and e are single bonds or N or CH when one of d or eis a double bond;

Z^(a) is C═O or CH₂;

G^(a) is NR^(2a) when c is a single bond, or G^(a) is CR^(2a) when c isa double bond;

R^(2a) is hydrogen, lower alkyl, lower alkenyl, heteroalkyl,—C(O)R^(12a), —CONR^(12a), or cycloalkyl, each of which is optionallysubstituted;

R^(3a) is hydrogen, lower alkyl, cycloalkyl, heteroalkyl, orheterocycloalkyl, each of which is optionally substituted; or

R^(2a) and R^(3a), together with the atoms to which they are attachedare linked to form a mononcyclic or bicyclic cycloalkyl or heterocyclicring, each of which is optionally substituted; and R¹² is hydrogen orlower alkyl; pharmaceutically acceptable salt thereof;

provided that at least one of c and d is a double bond.

In some embodiments, at least one of G^(a), Q^(a), and X^(a) is anitrogen atom. In some embodiments, at least two of G^(a), Q^(a), andX^(a) are nitrogen atoms. In some embodiments, both Q^(a) and G^(a) arenitrogen atoms. In some embodiments, both Q^(a) and X^(a) are nitrogenatoms.

In some embodiments, at least one of d and e is a double bond.

In some embodiments, L^(1a) is —C≡C—. In some embodiments, L^(1a) is—HC═CH—. In some embodiments, L^(1a) is —CH₂CH₂—. In some embodiments,L^(1a) is —C(O)NH—. In some embodiments, L^(1a) is —NHC(O)—. In someembodiments, L^(1a) is —CH(OH)CH₂—. In some embodiments, L^(1a) is—C(O)CH₂—. In some embodiments, L^(1a) is

In some embodiments, L^(1a) is

In some embodiments, L^(1a) is

In some embodiments, Y^(1a) is CH or N. In some embodiments, Y^(1a) is tCH. In some embodiments, Y^(1a) is N. In one embodiment Y¹ is C-halogen,such as C—F or C—Cl

In some embodiments, Y^(2a) is 1 CH. In some embodiments, Y^(2a) is CH.In some embodiments, Y^(2a) is N. In one embodiment Y^(2a) is C-halogen,such as C—F or C—Cl

In some embodiments, Y^(3a) is CH or N. In some embodiments, Y^(3a) isCH. In some embodiments, Y^(3a) is N. In one embodiment Y^(3a) isC-halogen, such as C—F or C—Cl.

In some embodiments, Z^(a) is C═O. In some embodiments, Z^(a) is CH₂.

In some embodiments, Q^(a) is N. In some embodiments, Q^(a) is CH.

In some embodiments, G^(a) is NR^(2a) when c is a single bond, or G^(a)is CR^(2a) when c is a double bond. In some embodiments, G^(a) isNR^(2a). In some embodiments, G^(a) is CR^(2a).

In some embodiments, X^(a) is N, G^(a) is CR^(2a), c and e are doublebonds and d and f are single bonds.

In some embodiments, X^(a) is C, G^(a) is NR^(2a), c and e are singlebonds, and d and f are double bonds.

In some embodiments, R^(1a) is aryl. In some embodiments R^(1a) isheteroaryl. In some embodiments, R^(1a) is cycloalkyl. In someembodiments, R^(1a) is

In some embodiments, R^(2a) is lower alkyl, heteroalkyl, or cycloalkyl,each of which is optionally substituted. In some embodiments, R^(2a) islower alkyl. In some embodiments, R^(2a) is heteroalkyl. In someembodiments, R^(2a) is cycloalkyl. In some embodiments, R^(2a) isalkenyl. In some embodiments, R^(2a) is —C(O)R^(12a). In someembodiments, R^(2a) is —CONR^(12a).

In some embodiments, R^(12a) is hydrogen. In some embodiments, R^(12a)is lower alkyl. In some embodiments, R^(12a) is methyl. In someembodiments, R^(12a) is ethyl.

In some embodiments, R^(2a) is hydrogen, methyl, propyl,cyclopropylmethyl, methoxymethyl, hydroxymethyl, methoxyethyl,hydroxyethyl, ethoxymethyl, ethoxyethyl, isobutyl, sec-butyl,dimethylaminoethyl, —CH₂═CH—,

In some embodiments, R^(3a) is hydrogen. In some embodiments, R^(3a) islower alkyl or cycloalkyl. In some embodiments, R^(3a) is heteroalkyl.In some embodiments, R^(3a) is heterocycloalkyl.

In some embodiments, R^(3a) is hydrogen, methoxymethyl, methoxyethyl,isobutyl, sec-butyl, dimethylaminoethyl, dimethylaminomethyl,

In another embodiment, R^(2a) and R^(3a) are linked to form a 5- to8-membered mono or bicyclic ring that is carbocyclic or heterocyclic,any of which is optionally substituted. In another embodiment, R^(2a)and R^(3a) are linked to form a mono or bicyclic ring that iscarbocyclic or heterocyclic, any of which is optionally substituted. Inanother embodiment, R^(2a) and R^(3a) are linked to form a monocyclicring that is carbocyclic and is optionally substituted. In anotherembodiment, R^(2a) and R^(3a) are linked to form a monocyclic ring thatis heterocyclic and is optionally substituted. In another embodimentR^(2a) and R^(3a) are linked to form a bicyclic ring that is carbocyclicthat is optionally substituted. In another embodiment R^(2a) and R^(3a)are linked to form a bicyclic ring that is heterocyclic that isoptionally substituted.

In some embodiments, R^(2a) and R^(3a) are linked to form

As used herein * is to denote that the enantiomers have been separatedbut the absolute stereochemistry of each enantiomer has not beenidentified.

In some embodiments, the invention provides compounds of formula Ib:

wherein

R^(1b) K is aryl or heteroaryl;

L^(1b) is —C≡C—, —CH═CH— or —C(O)NH—;

Y^(3b) is CH or N;

X^(b) is N when f is a single bond or C when f is a double bond;

G^(b) is NR^(2b) when c is a single bond or CR^(2a) when c is a doublebond;

R^(2b) is lower alkyl or heteroalkyl; and

R^(3b) is hydrogen, heteroalkyl, or heterocycloalkyl, each of which isoptionally substituted; or

R^(2b) and R^(3b), together with the atoms to which they are attachedare linked to form a monocyclic or bicyclic ring that is cycloalkyl orheterocyclic, each of which is optionally substituted; and

c, d e, and f are each independently single or double bonds; providedthat when c is a double bond, d is a single bond; when d is a doublebond, c and e are single bonds; when e is a double bond, d and f aresingle bonds; and when f is a double bond, e is a single bond, or apharmaceutically acceptable salt thereof;

provided that at least one of c and d is a double bond.

In some embodiments, one of G^(b) and X^(b) is a nitrogen atom.

In some embodiments, R^(1b) is aryl, for example,

In some embodiments, R^(1b) is heteroaryl, for example,

In some embodiments R^(2b) is lower alkyl, such as methyl. In someembodiments, R^(2b) is heteroalkyl, such as alkoxyalkyl, for example,

In some embodiments, R^(3b) is heteroalkyl, such as alkoxyalkyl, forexample,

In some embodiments, R^(3b) is heterocycloalkyl, for example,

In another embodiment, R^(2b) and R^(3b) are linked to form a 5- to8-membered mono or bicyclic ring that is carbocyclic or heterocyclic,any of which is optionally substituted. In another embodiment, R^(2b)and R^(3b) are linked to form a mono or bicyclic ring that iscarbocyclic or heterocyclic, any of which is optionally substituted. Inanother embodiment, R^(2b) and R^(3b) are linked to form a monocyclicring that is carbocyclic. In another embodiment, R^(2b) and R^(3b) arelinked to form a monocyclic ring that is heterocyclic. In anotherembodiment R^(2b) and R^(3b) are linked to form a bicyclic ring that iscarbocyclic. In another embodiment R^(2b) and R^(3b) are linked to forma bicyclic ring that is heterocyclic.

In some embodiments, R^(2b) and R^(3b) together with the atoms to whichthey are attached are linked to form a monocyclic or bicyclic ring thatis a cycloalkyl or heterocycloalkyl ring, for example,

As used herein * is to denote that the enantiomers have been separatedbut the absolute stereochemistry of each enantiomer has not beenidentified.

In some embodiments, the compounds of formula (Ib) have the followingsubstituents:

R^(1b) L^(2b) Y^(3b) X^(b) G^(b) R^(2b)&R^(3b) c, d e & f

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C N C NR^(2b)

c = single d = double e = single f = double

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH N CR^(2b)

c = double d = single e = double f = single

C≡C CH N CR^(2b)

c = double d = single e = double f = single

HC═CH CH C NR^(2b)

c = single d = double e = single f = double

—C(O)NH— CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C N C NR^(2b)

c = single d = double e = single f = double

C≡C N C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

C≡C CH C NR^(2b)

c = single d = double e = single f = double

In one embodiment, the invention provides a compound of formula (II):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

wherein

R^(1i), R^(2i) and R^(3i) are each independently hydrogen, lower alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, aryl or heteroaryl,each of which is optionally substituted, or

R^(2i) and R^(3i) are optionally joined, together with the atoms towhich they are attached, to form a mono or bicyclic ring that iscarbocyclic or heterocyclic, any of which is optionally substituted;

L^(1i) is —C≡C—, —HC═CH—, -(lower alkyl)-C═C-(lower alkyl)-, —CH₂—CH₂—,—CO—CH₂—, —CH₂—CO—, —NR^(12i)—CO—, —CO—NR^(12i)—C₀₋₆alkyl-O—C₀₋₆alkyl-,NR^(12i)SO, SONR^(12i), —NR^(12i)SO₂—, —SO₂NR^(12i)—,

R^(12i) is hydrogen or lower alkyl;

W^(1i) and W^(2i) are each independently N or CH;

W^(3i) is O, S or NR^(4i); and

R^(4i) is hydrogen or lower alkyl or a pharmaceutically acceptable saltthereof.

In one embodiment, R^(1i) is hydrogen. In another embodiment, R^(1i) isoptionally substituted lower alkyl. In another embodiment, R^(1i) isoptionally substituted heteroalkyl. In another embodiment, R^(1i) isoptionally substituted cycloalkyl. In another embodiment, R^(1i) isoptionally substituted monocyclic cycloalkyl. In another embodiment,R^(1i) is optionally substituted heterocycloalkyl. In anotherembodiment, R^(1i) is optionally substituted monocyclicheterocycloalkyl. In another embodiment, R^(1i) is optionallysubstituted alkylcycloalkyl. In another embodiment, R^(1i) is optionallysubstituted monocyclic alkylcycloalkyl. In another embodiment, R^(1i) isoptionally substituted alkylheterocycloalkyl. In another embodiment,R^(1i) is optionally substituted monocyclic alkylheterocycloalkyl. Inanother embodiment, R^(1i) is optionally substituted alkylaryl. Inanother embodiment, R^(1i) is optionally substituted monocyclicalkylaryl. In another embodiment, R^(1i) is optionally substitutedalkylheteroaryl. In another embodiment, R^(1i) is optionally substitutedmonocyclic alkylheteroaryl. In another embodiment, R^(1i) is optionallysubstituted aryl. In another embodiment, R^(1i) is optionallysubstituted monocyclic aryl. In another embodiment, R^(1i) is optionallysubstituted heteroaryl. In another embodiment, R^(1i) is optionallysubstituted monocyclic heteroaryl.

In one embodiment, R^(2i) is hydrogen. In another embodiment, R^(2i) isoptionally substituted lower alkyl. In another embodiment, R^(2i) isoptionally substituted heteroalkyl. In another embodiment, R^(2i) isoptionally substituted cycloalkyl. In another embodiment, R^(2i) isoptionally substituted monocyclic cycloalkyl. In another embodiment,R^(2i) is optionally substituted heterocycloalkyl. In anotherembodiment, R^(2i) is optionally substituted monocyclicheterocycloalkyl. In another embodiment, R^(2i) is optionallysubstituted alkylcycloalkyl. In another embodiment, R^(2i) is optionallysubstituted monocyclic alkylcycloalkyl. In another embodiment, R^(2i) isoptionally substituted alkylheterocycloalkyl. In another embodiment,R^(2i) is optionally substituted monocyclic alkylheterocycloalkyl. Inanother embodiment, R^(2i) is optionally substituted alkylaryl. Inanother embodiment, R^(2i) is optionally substituted monocyclicalkylaryl. In another embodiment, R^(2i) is optionally substitutedalkylheteroaryl. In another embodiment, R^(2i) is optionally substitutedmonocyclic alkylheteroaryl. In another embodiment, R^(2i) is optionallysubstituted aryl. In another embodiment, R^(2i) is optionallysubstituted monocyclic aryl. In another embodiment, R^(2i) is optionallysubstituted heteroaryl. In another embodiment, R^(2i) is optionallysubstituted monocyclic heteroaryl.

In one embodiment, R^(3i) is hydrogen. In another embodiment, R^(3i) isoptionally substituted lower alkyl. In another embodiment, R^(3i) isoptionally substituted heteroalkyl. In another embodiment, R^(3i) isoptionally substituted cycloalkyl. In another embodiment, R^(3i) isoptionally substituted monocyclic cycloalkyl. In another embodiment,R^(3i) is optionally substituted heterocycloalkyl. In anotherembodiment, R^(3i) is optionally substituted monocyclicheterocycloalkyl. In another embodiment, R^(3i) is optionallysubstituted alkylcycloalkyl. In another embodiment, R^(3i) is optionallysubstituted monocyclic alkylcycloalkyl. In another embodiment, R^(3i) isoptionally substituted alkylheterocycloalkyl. In another embodiment,R^(3i) is optionally substituted monocyclic alkylheterocycloalkyl. Inanother embodiment, R^(3i) is optionally substituted alkylaryl. Inanother embodiment, R^(3i) is optionally substituted monocyclicalkylaryl. In another embodiment, R^(3i) is optionally substitutedalkylheteroaryl. In another embodiment, R^(3i) is optionally substitutedmonocyclic alkylheteroaryl. In another embodiment, R^(3i) is optionallysubstituted aryl. In another embodiment, R^(3i) is optionallysubstituted monocyclic aryl. In another embodiment, R^(3i) is optionallysubstituted heteroaryl. In another embodiment, R^(3i) is optionallysubstituted monocyclic heteroaryl.

In another embodiment, R^(2i) and R^(3i) are combined to form a 5- to8-membered mono or bicyclic ring that is carbocyclic or heterocyclic,any of which is optionally substituted. In another embodiment, R^(2i)and R^(3i) are combined to form a mono or bicyclic ring that iscarbocyclic or heterocyclic, any of which is optionally substituted. Inanother embodiment, R^(2i) and R^(3i) are combined to form a monocyclicring that is carbocyclic. In another embodiment, R^(2i) and R^(3i) arecombined to form a monocyclic ring that is heterocyclic. In anotherembodiment R^(2i) and R^(3i) are combined to form a bicyclic ring thatis carbocyclic. In another embodiment R^(2i) and R^(3i) are combined toform a bicyclic ring that is heterocyclic.

In one embodiment, L^(1i) is —C≡C—, —HC═CH—, -(lower alkyl)-C═C-(loweralkyl)-, —CH₂—CH₂—, —CO—CH₂—, —CH₂—CO—, —NR^(12i)—CO—,

In one embodiment, L^(1i) is —C≡C—. In another embodiment, L^(1i) is—HC═HC—. In another embodiment, L^(1i) is —CH₂—CH₂—. In anotherembodiment, L^(1i) is —CO—CH₂—. In another embodiment, L^(1i) is—CH₂—CO—. In another embodiment, L^(1i) is —NR¹²—CO—. In anotherembodiment, L^(1i) is —CO—NR¹²—. In another embodiment, L^(1i) is—C₀₋₆alkyl-O—C₀₋₆ alkyl-. In another embodiment, L^(1i) is NR^(12i)SO—.In another embodiment, L^(1i) is —SONR^(12i). In another embodimentL^(1i) is —NR^(12i)SO₂—. In another embodiment, L^(1i) is —SO₂NR^(12i)—.R^(12i) is defined herein elsewhere.

In another embodiment, L^(1i) is:

In another embodiment, L^(1i) is:

In another embodiment, L^(1i) is:

In another embodiment, L^(1i) is:

In another embodiment, L^(1i) is:

In one embodiment, R^(12i) is hydrogen. In another embodiment, R^(12i)is lower alkyl.

In one embodiment, W^(1i) is N. In another embodiment, W^(1i) is CH.

In one embodiment, W^(2i) is N. In another embodiment, W^(2i) is CH.

In one embodiment, W^(3i) is O. In another embodiment, W^(3i) is S. Inanother embodiment, W^(3i) is NR^(4i). R^(4i) is defined hereinelsewhere.

In one embodiment, R^(4i) is hydrogen. In another embodiment, R^(4i) islower alkyl.

Any of the combinations of R^(1i), R^(2i), R^(3i), L^(1i), R^(12i),W^(1i), W^(2i), W^(3i) and R^(4i) are encompassed by this disclosure andspecifically provided by the invention.

In some embodiments, the compounds of formula II include, but are notlimited to, the following compounds:

In some embodiments, a compound of formula (Ha) is provided:

wherein

R^(1c) is aryl or heteroaryl;

L^(1c) is —C≡C—;

R^(2c) is lower alkyl or heteroalkyl; and

R^(3c) is hydrogen; or

R^(2c) and R^(3c) are linked to form a monocyclic or bicyclic ring thatis carbocyclic or heterocyclic;

or a pharmaceutically acceptable salt thereof.

In another embodiment, R^(2c) and R^(3c) are linked to form a 5- to8-membered mono or bicyclic ring that is carbocyclic or heterocyclic,any of which is optionally substituted. In another embodiment, R^(2c)and R^(3c) are linked to form a mono or bicyclic ring that iscarbocyclic or heterocyclic, any of which is optionally substituted. Inanother embodiment, R^(2c) and R^(3c) are linked to form a monocyclicring that is carbocyclic. In another embodiment, R^(2c) and R^(3c) arelinked to form a monocyclic ring that is heterocyclic. In anotherembodiment R^(2c) and R^(3c) are linked to form a bicyclic ring that iscarbocyclic. In another embodiment R^(2C) and R^(3c) are linked to forma bicyclic ring that is heterocyclic.

In some embodiments, the compounds of formula (Ha) have the followingsubstituents:

R^(1c) L^(1c) R^(2c)&R^(3c)

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

In one embodiment, there is provided a compound of formula (III):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

wherein R^(1d), R^(2d) and R^(3d) are each independently hydrogen, loweralkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, aryl or heteroaryl,each of which is optionally substituted; or

R^(2d) and R^(3d) are optionally joined, together with the atoms towhich they are attached, to form a mono or bicyclic ring that iscarbocyclic or heterocyclic, any of which is optionally substituted;

L^(1d) is —C≡C—, —HC═CH—, -(lower alkyl)-C═C-(lower alkyl)-, —CH₂—CH₂—,—CO—CH₂—, —CH₂—CO—, —NR^(12d)—CO—, —CO—NR^(12d)—,C₀₋₆alkyl-O—C₀₋₆alkyl-, —NR^(12d)SO—, —SONR^(12d)—, —NR^(12d)SO₂,SO₂NR^(12d)—,

R^(12d) is hydrogen or lower alkyl

W^(1d) and W^(2d) are each independently N or CH;

W^(3d) is O, S or NR^(4d);

R^(4d) is hydrogen or lower alkyl.

In one embodiment, R^(1d) is hydrogen. In another embodiment, R^(1d) isoptionally substituted lower alkyl. In another embodiment, R^(1d) isoptionally substituted heteroalkyl. In another embodiment, R^(1d) isoptionally substituted cycloalkyl. In another embodiment, R^(1d) isoptionally substituted monocyclic cycloalkyl. In another embodiment,R^(1d) is optionally substituted heterocycloalkyl. In anotherembodiment, R^(1d) is optionally substituted monocyclicheterocycloalkyl. In another embodiment, R^(1d) is optionallysubstituted alkylcycloalkyl. In another embodiment, R^(1d) is optionallysubstituted monocyclic alkylcycloalkyl. In another embodiment, R^(1d) isoptionally substituted alkylheterocycloalkyl. In another embodiment,R^(1d) is optionally substituted monocyclic alkylheterocycloalkyl. Inanother embodiment, R^(1d) is optionally substituted alkylaryl. Inanother embodiment, R^(1d) is optionally substituted monocyclicalkylaryl. In another embodiment, R^(1d) is optionally substitutedalkylheteroaryl. In another embodiment, R^(1d) is optionally substitutedmonocyclic alkylheteroaryl. In another embodiment, R^(1d) is optionallysubstituted aryl. In another embodiment, R^(1d) is optionallysubstituted monocyclic aryl. In another embodiment, R^(1d) is optionallysubstituted heteroaryl. In another embodiment, R^(1d) is optionallysubstituted monocyclic heteroaryl.

In one embodiment, R^(2d) is hydrogen. In another embodiment, R^(2d) isoptionally substituted lower alkyl. In another embodiment, R^(2d) isoptionally substituted heteroalkyl. In another embodiment, R^(2d) isoptionally substituted cycloalkyl. In another embodiment, R^(2d) isoptionally substituted monocyclic cycloalkyl. In another embodiment,R^(2d) is optionally substituted heterocycloalkyl. In anotherembodiment, R^(2d) is optionally substituted monocyclicheterocycloalkyl. In another embodiment, R^(2d) is optionallysubstituted alkylcycloalkyl. In another embodiment, R^(2d) is optionallysubstituted monocyclic alkylcycloalkyl. In another embodiment, R^(2d) isoptionally substituted alkylheterocycloalkyl. In another embodiment,R^(2d) is optionally substituted monocyclic alkylheterocycloalkyl. Inanother embodiment, R^(2d) is optionally substituted alkylaryl. Inanother embodiment, R^(2d) is optionally substituted monocyclicalkylaryl. In another embodiment, R^(2d) is optionally substitutedalkylheteroaryl. In another embodiment, R^(2d) is optionally substitutedmonocyclic alkylheteroaryl. In another embodiment, R^(2d) is optionallysubstituted aryl. In another embodiment, R^(2d) is optionallysubstituted monocyclic aryl. In another embodiment, R^(2d) is optionallysubstituted heteroaryl. In another embodiment, R^(2d) is optionallysubstituted monocyclic heteroaryl.

In one embodiment, R^(3d) is hydrogen. In another embodiment, R^(3d) isoptionally substituted lower alkyl. In another embodiment, R^(3d) isoptionally substituted heteroalkyl. In another embodiment, R^(3d) isoptionally substituted cycloalkyl. In another embodiment, R^(3d) isoptionally substituted monocyclic cycloalkyl. In another embodiment,R^(3d) is optionally substituted heterocycloalkyl. In anotherembodiment, R^(3d) is optionally substituted monocyclicheterocycloalkyl. In another embodiment, R^(3d) is optionallysubstituted alkylcycloalkyl. In another embodiment, R^(3d) is optionallysubstituted monocyclic alkylcycloalkyl. In another embodiment, R^(3d) isoptionally substituted alkylheterocycloalkyl. In another embodiment,R^(3d) is optionally substituted monocyclic alkylheterocycloalkyl. Inanother embodiment, R^(3d) is optionally substituted alkylaryl. Inanother embodiment, R^(3d) is optionally substituted monocyclicalkylaryl. In another embodiment, R^(3d) is optionally substitutedalkylheteroaryl. In another embodiment, R^(3d) is optionally substitutedmonocyclic alkylheteroaryl. In another embodiment, R^(3d) is optionallysubstituted aryl. In another embodiment, R^(3d) is optionallysubstituted monocyclic aryl. In another embodiment, R^(3d) is optionallysubstituted heteroaryl. In another embodiment, R^(3d) is optionallysubstituted monocyclic heteroaryl.

In another embodiment, R^(2d) and R^(3d) are linked to form a 5- to8-membered mono or bicyclic ring that is carbocyclic or heterocyclic,any of which is optionally substituted. In another embodiment, R^(2d)and R^(3d) are linked to form a mono or bicyclic ring that iscarbocyclic or heterocyclic, any of which is optionally substituted. Inanother embodiment, R^(2d) and R^(3d) are linked to form a monocyclicring that is carbocyclic. In another embodiment, R^(2d) and R^(3d) arelinked to form a monocyclic ring that is heterocyclic. In anotherembodiment R^(2d) and R^(3d) are linked to form a bicyclic ring that iscarbocyclic. In another embodiment R^(2d) and R^(3d) are linked to forma bicyclic ring that is heterocyclic.

In one embodiment, L^(1d) is —C≡C—, —HC═CH—, —CH₂—CH₂—, —CO—CH₂—,—CH₂—CO—, NR^(12d)—C—, CO—NR^(12d)—,

In one embodiment, L^(1d) is —C≡C—. In another embodiment, L^(1d) is—HC═CH—. In another embodiment, L^(1d) is —CH₂—CH₂—. In anotherembodiment, L^(1d) is —CO—CH₂—. In another embodiment, L^(1d) is—CH₂—CO—. In another embodiment, L^(1d) is —NR^(12d)CO—. In anotherembodiment, L^(1d) is —CO—NR^(12d)—. In another embodiment, L^(1d) is—C₀₋₆alkyl-O—C₀₋₆alkyl-. In another embodiment, L^(1d) is NR^(12d)SO. Inanother embodiment, L^(1d) is —SONR^(12d)—. In another embodiment,L^(1d) is —NR^(12d)SO₂—. In another embodiment, L^(1d) is —SO₂NR^(12d)—.R^(12d) is defined herein elsewhere.

In another embodiment, L^(1d) is:

In another embodiment, L^(1d) is:

In another embodiment, L^(1d) is:

In another embodiment, L^(1d) is:

In another embodiment, L^(1d) is:

In one embodiment, R^(12d) is hydrogen. In another embodiment, R^(12d)is lower alkyl.

In one embodiment, W^(1d) is N. In another embodiment, W^(1d) is CH.

In one embodiment, W^(2d) is N. In another embodiment, W^(2d) is CH.

In one embodiment, W^(3d) is O. In another embodiment, W^(3d) is S. Inanother embodiment, W^(3d) is NR^(4d). R^(4d) is defined hereinelsewhere.

In one embodiment, R^(4d) is hydrogen. In another embodiment, R^(4d) islower alkyl.

Any of the combinations of R^(1d), R^(2d), R^(3d), L^(1d), R^(12d),W^(1d), W^(2d), W^(3d) and R^(4d) are encompassed by this disclosure andspecifically provided by the invention.

In some embodiments, the compounds of formula II include, but are notlimited to, the following compounds:

In some embodiments, compounds of formula (Ma) are provided:

wherein

R^(1e) is aryl or heteroaryl;

L^(1e) is —HC≡CH—, —C═C—, or —C(O)NH—;

R^(2e) is lower alkyl or heteroalkyl;

R^(3e) is hydrogen, lower alkyl heteroalkyl, or heterocycloalkyl; or

R^(2e) and R^(3e) are linked to form a monocyclic or bicyclicheterocyclic or cycloalkyl ring, each of which is optionallysubstituted; and pharmaceutically acceptable salts thereof.

In some embodiments, R^(2e) and R^(3e) are linked to form a 5- to8-membered mono or bicyclic ring that is carbocyclic or heterocyclic,any of which is optionally substituted. In another embodiment, R^(2e)and R^(3e) are linked to form a mono or bicyclic ring that iscarbocyclic or heterocyclic, any of which is optionally substituted. Inanother embodiment, R^(2e) and R^(3e) are linked to form a monocyclicring that is carbocyclic. In another embodiment, R^(2e) and R^(3e) arelinked to form a monocyclic ring that is heterocyclic. In anotherembodiment R^(2e) and R^(3e) are linked to form a bicyclic ring that iscarbocyclic. In another embodiment R^(2e) and R^(3e) are linked to forma bicyclic ring that is heterocyclic.

In some embodiments, the compounds of formula (Ina) have the followingsubstituents

R^(1e) L^(1e) R^(2e)&R^(3e)

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

C≡C

HC═CH

CONH

C≡C

In one embodiment, there is provided a compound of formula (IV):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

R^(1f) is hydrogen, lower alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl,alkylheteroaryl, aryl or heteroaryl, each of which is optionallysubstituted;

J¹, J², J³, J⁴, J⁵, and J⁶ are independently CO, O, S, NR⁷, CR⁸R⁹ orC═CR¹⁰R¹¹, provided that there are no adjacent heteroatoms in theresulting ring;

m, n, and p are independently 0 or 1;

R⁷ is hydrogen, cycloalkyl, heteroalkyl, acyl, heterocycloalkyl,C(O)Oalkyl, C(O)H, or lower alkyl;

R⁸ and R⁹ are each independently hydrogen, lower alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl,alkylaryl or alkylheteroaryl, each of which is optionally substituted;or R⁸ and R⁹ together with the carbon atom to which they are attachedare linked to form a 5-6 membered heterocyclic or cycloalkyl ring, eachof which is optionally substituted;

R¹⁰ and R¹¹ are each independently hydrogen or lower alkyl;

c, d, e, and f are each independently a singe or a double bond, providedthat when c is a double bond, d is a single bond, when d is a doublebond, c and e are single bond, when e is a double bond, d and f aresingle bonds, and when f is a double bond, e is a single bond;

G is N when c is a single bond, or C when c is a double bond;

Q is NH or CH₂ when d and e are single bonds, or N or CH when one of dor e are a double bond;

X is N when f is a single bond or C when f is a double bond;

L^(1f) is —C≡C—, —HC═CH—, -(lower alkyl)-C═C-(lower alkyl)-, —CH₂—CH₂—,—CO—CH₂—, —CH₂—CO—, —C₀₋₆alkyl-O—C₀₋₆alkyl-, —NHR¹²SO—, —SONR¹²—,—NR¹²SO₂—, —SO₂NR¹²—, —NR¹²—CO—, —CO—NR¹²—,

R^(12f) is hydrogen or lower alkyl;

W^(1f) and W^(2f) are each independently selected from N and CH;

W^(3f) is selected from O, S, and NR^(4f); and

R⁴ is selected from hydrogen and lower alkyl, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, at least one of G, Q, and X is a nitrogen atom. Insome embodiments, at least two of G, Q, and X is a nitrogen atom. Insome embodiments, both Q and G are nitrogen atoms. In some embodiments,both Q and X are nitrogen atoms.

In one embodiment, R^(1f) is hydrogen. In another embodiment, R^(1f) isoptionally substituted lower alkyl. In another embodiment, R^(1f) isoptionally substituted heteroalkyl. In another embodiment, R^(1f) isoptionally substituted cycloalkyl. In another embodiment, R^(1f) isoptionally substituted monocyclic cycloalkyl. In another embodiment,R^(1f) is optionally substituted heterocycloalkyl. In anotherembodiment, R^(1f) is optionally substituted monocyclicheterocycloalkyl. In another embodiment, R^(1f) is optionallysubstituted alkylcycloalkyl. In another embodiment, R^(1f) is optionallysubstituted monocyclic alkylcycloalkyl. In another embodiment, R^(1f) isoptionally substituted alkylheterocycloalkyl. In another embodiment,R^(1f) is optionally substituted monocyclic alkylheterocycloalkyl. Inanother embodiment, R^(1f) is optionally substituted alkylaryl. Inanother embodiment, R^(1f) is optionally substituted monocyclicalkylaryl. In another embodiment, R^(1f) is optionally substitutedalkylheteroaryl. In another embodiment, R^(1f) is optionally substitutedmonocyclic alkylheteroaryl. In another embodiment, R^(1f) is optionallysubstituted aryl. In another embodiment, R^(1f) is optionallysubstituted monocyclic aryl. In another embodiment, R^(1f) is optionallysubstituted heteroaryl. In another embodiment, R^(1f) is optionallysubstituted monocyclic heteroaryl.

In one embodiment, J¹ is O. In another embodiment, J¹ is S. In anotherembodiment, J¹ is NR⁷. In another embodiment, J¹ is CR⁸R⁹. In anotherembodiment, J¹ is CH₂. In another embodiment, J¹ is CHR⁸. In anotherembodiment, J¹ is C═CR¹⁰R¹¹. R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are defined hereinelsewhere.

In one embodiment, J² is O. In another embodiment, J² is S. In anotherembodiment, J² is NR⁷. In another embodiment, J² is CR⁸R⁹. In anotherembodiment, J² is CH₂. In another embodiment, J² is CHR⁸. In anotherembodiment, J² is C═CR¹⁰R¹¹. R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are defined hereinelsewhere.

In one embodiment, J³ is O. In another embodiment, J³ is S. In anotherembodiment, J³ is NR⁷. In another embodiment, J³ is CR⁸R⁹. In anotherembodiment, J³ is CH₂. In another embodiment, J³ is CHR⁸. In anotherembodiment, J³ is C═CR¹⁰R¹¹. R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are defined hereinelsewhere.

In one embodiment, J⁴ is O. In another embodiment, J⁴ is S. In anotherembodiment, J⁴ is NR⁷. In another embodiment, J⁴ is CR⁸R⁹. In anotherembodiment, J⁴ is CH₂. In another embodiment, J⁴ is CHR⁸. In anotherembodiment, J⁴ is C═CR¹⁰R¹¹. R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are defined hereinelsewhere.

In one embodiment, J⁵ is O. In another embodiment, J⁵ is S. In anotherembodiment, J⁵ is NR⁷. In another embodiment, J⁵ is CR⁸R⁹. In anotherembodiment, J⁵ is CH₂. In another embodiment, J⁵ is CHR⁸. In anotherembodiment, J⁵ is C═CR¹⁰R¹¹. R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are defined hereinelsewhere.

In one embodiment, J⁶ is O. In another embodiment, J⁶ is S. In anotherembodiment, J⁶ is NR⁷. In another embodiment, J⁶ is CR⁸R⁹. In anotherembodiment, J⁶ is CH₂. In another embodiment, J⁶ is CHR⁸. In anotherembodiment, J⁶ is C═CR¹⁰R¹¹. R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are defined hereinelsewhere.

In an exemplary embodiment according to the description above, there areno adjacent heteroatoms in the resulting ring.

In one embodiment, m is 0. In another embodiment, m is 1.

In one embodiment, n is 0. In another embodiment, n is 1.

In one embodiment, p is 0. In another embodiment, p is 1.

In one embodiment, R⁷ is hydrogen. In another embodiment, R⁷ is loweralkyl.

In one embodiment, R⁸ is hydrogen. In another embodiment, R⁸ isoptionally substituted lower alkyl. In another embodiment, R⁸ isoptionally substituted heteroalkyl. In another embodiment, R⁸ isoptionally substituted cycloalkyl. In another embodiment, R⁸ isoptionally substituted monocyclic cycloalkyl. In another embodiment, R⁸is optionally substituted heterocycloalkyl. In another embodiment, R⁸ isoptionally substituted monocyclic heterocycloalkyl. In anotherembodiment, R⁸ is optionally substituted alkylcycloalkyl. In anotherembodiment, R⁸ is optionally substituted monocyclic alkylcycloalkyl. Inanother embodiment, R⁸ is optionally substituted alkylheterocycloalkyl.In another embodiment, R⁸ is optionally substituted monocyclicalkylheterocycloalkyl. In another embodiment, R⁸ is optionallysubstituted alkylaryl. In another embodiment, R⁸ is optionallysubstituted monocyclic alkylaryl. In another embodiment, R⁸ isoptionally substituted alkylheteroaryl. In another embodiment, R⁸ isoptionally substituted monocyclic alkylheteroaryl.

In one embodiment, R⁹ is hydrogen. In another embodiment, R⁹ isoptionally substituted lower alkyl. In another embodiment, R⁹ isoptionally substituted heteroalkyl. In another embodiment, R⁹ isoptionally substituted cycloalkyl. In another embodiment, R⁹ isoptionally substituted monocyclic cycloalkyl. In another embodiment, R⁹is optionally substituted heterocycloalkyl. In another embodiment, R⁹ isoptionally substituted monocyclic heterocycloalkyl. In anotherembodiment, R⁹ is optionally substituted alkylcycloalkyl. In anotherembodiment, R⁹ is optionally substituted monocyclic alkylcycloalkyl. Inanother embodiment, R⁹ is optionally substituted alkylheterocycloalkyl.In another embodiment, R⁹ is optionally substituted monocyclicalkylheterocycloalkyl. In another embodiment, R⁹ is optionallysubstituted alkylaryl. In another embodiment, R⁹ is optionallysubstituted monocyclic alkylaryl. In another embodiment, R⁹ isoptionally substituted alkylheteroaryl. In another embodiment, R⁹ isoptionally substituted monocyclic alkylheteroaryl.

In one embodiment, R¹⁰ is hydrogen. In another embodiment, R¹⁰ is loweralkyl.

In one embodiment, R¹¹ is hydrogen. In another embodiment, R¹¹ is loweralkyl.

In one embodiment, G is C. In another embodiment, G is N.

In one embodiment, Q is N. In another embodiment, Q is CH.

In one embodiment, X is C. In another embodiment, X is N.

In one embodiment L^(1f) is —C≡C—, —HC═CH—, —CH₂—CH₂—, —CO—CH₂—,—CH₂—CO—, —NR^(12f)—CO—, —CO—NR^(12f)—,

In one embodiment, L^(1f) is —C≡C—. In another embodiment, L^(1f) is—HC═CH—. In another embodiment, L^(1f) is —CH₂—CH₂—. In anotherembodiment, L^(1f) is —CO—CH₂—. In another embodiment, L^(1f) is—CH₂—CO—. In another embodiment, L^(1f) is —NR^(12f)—CO—. In anotherembodiment, L^(1f) is —CO—NR^(12f)—. In another embodiment, L^(1f) is—C₀₋₆alkyl-O—C₀₋₆ alkyl-. In another embodiment, L^(1f) is—NHR^(12f)SO—. In another embodiment, L^(1f) is —SONR^(12f)—. In anotherembodiment, L^(1f) is —NR^(12f)SO₂—. In another embodiment, L^(1f) is—SO₂NR^(12f)—. R^(12f) is defined herein elsewhere.

In another embodiment, L^(1f) is:

In another embodiment, L^(1f) is:

In another embodiment, L^(1f) is:

In another embodiment, L^(1f) is: In another embodiment, L^(1f) is:

In one embodiment, R^(12f) is hydrogen In another embodiment, R^(12f) islower alkyl.

In one embodiment, W^(1f) is N. In another embodiment, W^(1f) is CH.

In one embodiment, W^(2f) is N. In another embodiment, W^(2f) is CH.

In one embodiment, W^(3f) is O. In another embodiment, W^(3f) is S. Inanother embodiment, W^(3f) is NR^(4f). R^(4f) is defined hereinelsewhere.

In one embodiment, R^(4f) is hydrogen. In another embodiment, R^(4f) islower alkyl.

Any of the combinations of R^(1f), J¹, J², J³, J⁴, J⁵, J⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, G⁴, Q⁴, X⁴, L^(1f), R^(12f), W^(1f), W^(2f), W^(3f), andR^(4f) are encompassed by this disclosure and specifically provided bythe invention.

In an exemplary embodiment according to the description above, J¹, J²,J³, J⁴, J⁵ and J⁶ are CH₂, m is 1, n is 1, and p is 0. In anotherexemplary embodiment according to the description above, J¹, J², J³, J⁴,J⁵ and J⁶ are CH₂, m is 1, n is 1, and p is 1.

In an exemplary embodiment according to the description above, J², J³,J⁴, J⁵ and J⁶ are CH₂, m is 1, n is 1, p is selected from 0 and 1, andJ¹ is selected from CHR⁸, and C═CR¹⁰R¹¹.

In an exemplary embodiment according to the description above, J¹, J³,J⁴, J⁵ and J⁶ are CH₂, m is 1, n is 1, p is selected from 0 and 1, andJ² is CHR⁸.

In an exemplary embodiment according to the description above, J¹, J²,J⁴, J⁵ and J⁶ are CH₂, m is 1, n is 1, p is selected from 0 and 1, andJ³ is selected from NR⁷, O, and CHR⁸.

In an exemplary embodiment according to the description above, J¹, J²,J³, J⁴ and J⁶ are CH₂, m is 1, n is 1, p is selected from 0 and 1, andJ⁵ is selected from NR⁷, O, and CHR⁸.

In some embodiments, compounds of formula IVa are provided:

wherein

R^(1g) is aryl or heteroaryl;

L^(1g) is —C≡C—, is CONH— or

J⁷, J⁸, J⁹, J¹⁰, J¹¹ and J¹² are each independently CO, O, S, NR²⁰,CR²¹R²² or C═CR²³R²⁴, provided that there are no adjacent heteroatoms inthe resulting ring;

s, t, and u are each independently 0 or 1;

R²⁰ is hydrogen, cycloalkyl, heteroalkyl, acyl, heterocyclic,C(O)Oalkyl, C(O)H, C(O)NHalkyl or lower alkyl;

R²¹ and R²² are each hydrogen, lower alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl oralkylheteroaryl, each of which is optionally substituted; or R²⁰ and R²¹together with the carbon atom to which they are attached are linked toform a 5-6 membered heterocyclic or cycloalkyl ring; and

R²³ and R²⁴ are each independently hydrogen or lower alkyl, andpharmaceutically acceptable salts thereof.

In some embodiments, provided are compounds of formula IVb:

wherein

R^(1h) is aryl, heteroaryl or heterocyclic;

L^(1h) is —C≡C—, —HC═CH—, —CH₂CH₂—, —C(O)NH—, —NHC(O)—, CH(OH)CH₂—,C(O)CH₂,

J¹³, J¹⁴, J¹⁵, J¹⁶, J¹⁷ and J¹⁸ are each independently CO, O, S, NR²⁵,CR²⁶R²⁷ or C═CR²⁸R²⁹, provided that there are no adjacent heteroatoms inthe resulting ring;

v, w, and x are each independently 0 or 1;

R²⁵ is hydrogen, cycloalkyl, heteroalkyl, acyl, heterocyclic,C(O)Oalkyl, C(O)H, C(O)NHalkyl or lower alkyl;

R²⁶ and R²⁷ are each hydrogen, lower alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl oralkylheteroaryl, each of which is optionally substituted; or R²⁶ and R²⁷together with the carbon atom to which they are attached are linked toform a 5-6 membered heterocyclic or cycloalkyl ring; and

R²⁸ and R²⁹ are each independently hydrogen or lower alkyl, or apharmaceutically acceptable salt thereof.

In some embodiments, compounds of the invention include the compoundsset forth in the examples.

Methods of Treatment, Prevention, and/or ManagementBinding to mGluR5 Receptor

In various embodiments, a method of binding a compound as disclosedherein to a metabotropic glutamate receptor, such as mGluR5 is provided.The method comprises contacting mGluR with an amount of compound asdisclosed herein effective to bind a metabotropic glutamate receptor.

In one embodiment, a method of modulating the activity of mGluR5 via thebinding of an mGluR5 ligand to mGluR5 is provided. The method comprisescontacting mGluR5 with an amount of a compound as disclosed hereineffective to modulate the activity of mGluR5. In one embodiment, theligand is L-glutamate. In another embodiment, the ligand is a drugmolecule or another small molecule known to have binding affinity tomGluR5. In another embodiment, the mGluR5 ligand is a radioactivelylabeled compound, known to bind to mGluR5. In other embodiments, bindingto metabotropic glutamate receptor may be assessed using PET imaging asis known in the art, e.g. utilizing appropriate PET ligands. In someembodiments, the ligand is an allosteric modulator (e.g., a positive ornegative allosteric modulator), antagonist, or inverse agonist ofmGluR5.

Modulation of mGluR5 Receptor Activity

In various embodiments, a method of modulating (e.g., inhibiting oraugmenting) the activity of a metabotropic glutamate receptor, such asmGluR5 is provided. The method comprises contacting the receptor, suchas mGluR5, with an amount of a compound as disclosed herein, or apharmaceutically acceptable salt thereof effective to modulate theactivity of a metabotropic glutamate receptor, in vitro or in vivo. Inone embodiment, mGluR5 is contacted with a compound as disclosed hereinby administering to a subject a therapeutically effective amount of acompound as disclosed herein, or a pharmaceutically acceptable salt orsolvate thereof. The subject may be a human.

In one embodiment, a compound as disclosed herein increases or augmentsthe activity of metabotropic glutamate receptor, such as mGluR5. In someembodiments, the activity of mGluR5 is increased or augmented by about1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%,about 60%, about 70%, about 80%, about 90%, about 95%, about 99% ormore, as compared with the activity obtained in the absence of acompound as disclosed herein. In one embodiment, the increase oraugmentation of receptor activity is dose-dependent. Increase of mGluR5activity may be measured using assays known in the art, for example, byin vitro functional assays as described herein elsewhere. In oneembodiment, the functional assay utilizes an appropriate cell-lineexpressing the desired metabotropic glutamate receptor, such as mGluR5.In other embodiments, the functional assay utilizes synaptosomesisolated from brain tissue of an appropriate organism. In otherembodiments, inhibition of metabotropic glutamate receptor activity maybe assessed using receptor binding experiments known in the art, e.g.,utilizing appropriate membrane preparations. In one embodiment, theassay involves treatment of a test subject (e.g., a mice or a rat) witha compound as disclosed herein as well as a reference compound, followedby isolation of brain tissue and ex vivo analysis of receptor occupancy.In one embodiment, the mGluR5 modulator is a positive allostericmodulator.

In certain embodiments, methods of increasing or augmenting the activityof a metabotropic glutamate receptor, such as mGluR5, in a subject(e.g., human) comprising administering to the subject an effectiveamount of compound as disclosed herein are provided. In someembodiments, the activity of mGluR5 is increased or augmented by about1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%,about 60%, about 70%, about 80%, about 90%, about 95%, about 99% ormore, when measured using an assay known in the art compared to theactivity obtained in the absence of administration of a compound asdisclosed herein.

In one embodiment, a method of increasing or augmenting the activity ofa metabotropic glutamate receptor, such as mGluR5, by a metabotropicglutamate receptor ligand is provided. In one embodiment, the methodcomprises contacting mGluR5 receptor with a potentiator, an allostericagonist, or a positive allosteric modulator of the mGluR5 receptor in anamount effective to increase or augment the activity. In anotherembodiment, a potentiator, an allosteric agonist, or a positiveallosteric modulator of the mGluR5 receptor is a compound as disclosedherein.

In one embodiment, a compound as disclosed herein inhibits or reducesthe activity of metabotropic glutamate receptor, such as mGluR5. In someembodiments, the activity of mGluR5 is inhibited or reduced by about 1%,about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, ascompared with the activity obtained without contacting with thecompounds as disclosed herein. In one embodiment, the inhibition orreduction of receptor activity is dose-dependent Inhibition of mGluR5activity may be measured using assays known in the art, for example, thein vitro functional assays as described herein elsewhere. In oneembodiment, the functional assay utilizes an appropriate cell-lineexpressing the desired metabotropic glutamate receptor, such as mGluR5.In other embodiments, the functional assay utilizes synaptosomesisolated from brain tissue of an appropriate organism. In otherembodiments, inhibition of metabotropic glutamate receptor activity maybe assessed using receptor binding experiments known in the art, e.g.utilizing appropriate membrane preparations. In one embodiment, theassay involves treatment of a test subject (e.g., a mice or a rat) witha compound set forth herein as well as a reference compound, followed byisolation of brain tissue and ex vivo analysis of receptor occupancy. Inone embodiment, the mGluR5 modulator is a negative allosteric modulator.

In certain embodiments, methods of inhibiting or reducing the activityof a metabotropic glutamate receptor, such as mGluR5, in a subject(e.g., human) comprising administering to the subject an effectiveamount of a compound as disclosed herein are provided. In someembodiments, the activity of mGluR5 is inhibited or reduced by about 1%,about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about60%, about 70%, about 80%, about 90%, about 95%, about 99% or more, whenmeasured using an assay known in the art and compared to the activityobtained in the absence of administration of a compound as disclosedherein.

In one embodiment, a method of inhibiting or reducing the activity of ametabotropic glutamate receptor, such as mGluR5, by a metabotropicglutamate receptor ligand is provided. In one embodiment, the methodcomprises contacting mGluR5 receptor with an amount of an antagonist, aninverse agonist, or an allosteric modulator of the mGluR5 receptoreffective to inhibit or reduce the activity of the metabotropicglutamate receptor. In another embodiment, an antagonist, an inverseagonist, or an allosteric modulator of the mGluR5 receptor is a compoundas disclosed herein.

Treatment, Prevention, and/or Management of mGluR5 Related Disorders andConditions

In certain embodiments, a method of treating, preventing, and/ormanaging a neurological disorder, such as a neurodegenerative disorder,neuropsychiatric disorder, affective disorder, or a cognitive function,tearing or memory disorder, comprising administering to a subject inneed thereof an effective amount of a compound as disclosed herein isprovided.

In certain embodiments, a method of treating psychosis, schizophrenia,or a cognitive disorder (such as Alzheimer's disease), comprisingadministering to a subject in need thereof an effective amount of acompound as disclosed herein is provided. In one embodiment, thecompounds as disclosed herein inhibit the activity of mGluR5. In certainembodiments, the compounds as disclosed herein are positive allostericmodulators of mGluR5. In other embodiments, the compounds as disclosedherein are antagonists of mGluR5. In certain embodiments, the compoundsas disclosed herein are selective for mGluR5 over other CNS-relatedtargets. In one embodiment, the compounds as disclosed herein are highlybrain penetrable in mammals, such as rodents, and human. In someembodiments, inhibition or potentiation of mGluR5 activity may beassessed by functional assays as described herein elsewhere. In certainembodiments, the efficacious concentration of the compounds set forthherein is less than 10 nM, less than 100 nM, less than 1 μM, less than10 μM, less than 100 μM, or less than 1 mM. In other embodiments,compound's activity may be assessed in various art-recognized animalmodels.

In some embodiments, a method of treating, preventing, and/or managing aneurodegenerative disease [including but not limited to Alzheimer'sdisease (including the accompanying symptoms of mild, moderate, orsevere cognitive impairment); amyotropic lateral sclerosis (ALS); anoxicand ischemic injuries; ataxia and convulsion (including for thetreatment and prevention of seizures that are caused by schizoaffectivedisorder or by drugs used to treat schizophrenia); benign forgetfulness;brain edema; cerebellar ataxia including McLeod neuroacanthocytosissyndrome (MLS); closed head injury; coma; contusive injuries (e.g.spinal cord injury and head injury); dementias including multi-infarctdementia and senile dementia; disturbances of consciousness; Downsyndrome; drug-induced or medication-induced Parkinsonism (such asneuroleptic-induced acute akathisia, acute dystonia, Parkinsonism, ortardive dyskinesia, neuroleptic malignant syndrome, ormedication-induced postural tremor); epilepsy; fragile X syndrome;Gilles de la Tourette's syndrome; head trauma; hearing impairment andloss; Huntington's disease; Lennox syndrome; levodopa-induceddyskinesia; mental retardation; movement disorders including akinesiasand akinetic (rigid) syndromes (including basal ganglia calcification,corticobasal degeneration, multiple system atrophy, parkinsonism-ALSdementia complex, Parkinson's disease, postencephalitic parkinsonism,and progressively supranuclear palsy); muscular spasms and disordersassociated with muscular spasticity or weakness including chorea (suchas benign hereditary chorea, drug-induced chorea, hemiballism,Huntington's disease, neuroacanthocytosis, Sydenham's chorea, andsymptomatic chorea), dyskinesia (including tics such as complex tics,simple tics, and symptomatic tics), myoclonus (including generalizedmyoclonus and focal cyloclonus), tremor (such as rest tremor, posturaltremor, and intention tremor), and dystonia (including axial dystonia,dystonic writer's cramp, hemiplegic dystonia, paroxymal dystonia, andfocal dystonia such as blepharospasm, oromandibular dystonia, andspasmodic dysphonia and torticollis); neuronal damage including oculardamage, retinopathy or macular degeneration of the eye; neurotoxicinjury which follows cerebral stroke, thromboembolic stroke, hemorrhagicstroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia,hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson'sdisease; seizure; status epilecticus; stroke; tinnitus; and viralinfection induced neurodegeneration (including but limited toneurodegeneration caused by caused by acquired immunodeficiency syndrome(AIDS) and encephalopathies)], comprising administering to a subject inneed thereof an effective amount of a compound as disclosed herein isprovided. For example, without being limited by a particular theory,mGluR5 modulators may be effective in treating Parkinson's disease, andefficacious in a variety of animal models for Parkinson's disease. See,e.g., Jaeschke, G., et al., Expert Opin. Ther. Pat. 2008, 18, 123;Glatthar R., et al., WO 2006/89700 A1.

In some embodiments, a method of treating, preventing, and/or managing aneuropsychiatric disorder (including but limited to: aggression;attention disorders including attention-deficit disorder (ADD),attention-deficit-hyperactivity disorder (ADHD) and conduct disorder;delirium; delusional disorder; persisting dementia; pervasivedevelopment disorder including autism, autistic disorder and autismspectrum disorder; psychosis and psychotic disorders (includingpsychosis associated with affective disorders, brief reactive psychosis,brief psychotic disorder, shared psychotic disorder, psychotic disorderdue to a general medical condition and substance-induced or drug-inducedpsychotic disorder (e.g., caused by phencyclidine, ketamine and otherdissociative anaesthetics, amphetamine, cocaine and otherpsychostimulants)); schizophrenia (including schizoaffective psychosisand “schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, or illnesses associated with psychosis (such asmajor depression, manic depressive (bipolar) disorder, Alzheimer'sdisease and post-traumatic stress syndrome) including both the positiveand negative symptoms of schizophrenia and other psychoses); and sensoryhyper-excitability), comprising administering to a subject in needthereof an effective amount of a compound as disclosed herein isprovided.

In some embodiments, a method of treating, preventing and/or managingdisorders of cognition, learning or memory or of improving cognitivefunction, memory and learning abilities (including but not limited to:adult and childhood learning disorders; altruism; amnestic disorders(including Alzheimer's disease-related cognitive decline, normalage-related cognitive decline and persisting amnestic disorder);associative learning; attention; benign forgetfulness; cognitivedeficits induced by situational stress (including but not limited tooperating machinery for extended time periods or working in emergency orcombat situations); cognitive disorders including dementia (associatedwith acquired immunodeficiency disease, Alzheimer's disease,Creutzfeldt-Jacob disease, HIV infection, Huntington's disease,ischemia, multi-infarct dementia, Parkinson's disease, perinatalhypoxia, Pick's disease, trauma, vascular problems or stroke, othergeneral medical conditions or substance abuse); cooperativity;declarative memory; early consolidation; empathy; episodic memory;executive function; explicit memory; implicit memory; imprinting;language; late consolidation; learning (including electronic, formal,informal, multimedia and rote learning); low IQ; memory deficit; memoryloss; mild cognitive impairment (MCI); non-verbal and verbalcommunicative skills; play; rehearsal; retrieval, semantic memory;sensory integration of environmental cues including temperature, odor,sounds, touch, and taste; social cognition; and speech disorders),comprising administering to a subject in need thereof an effectiveamount of a compound as disclosed herein is provided.

In some embodiments, a method of treating, preventing, and/or managinggastrointestinal disorders (including but not limited to acid reflux;dyspepsia; gastroesophageal reflux disorder (GERD); and irritable bowelsyndrome), comprising administering to a subject in need thereof aneffective amount of a as disclosed herein is provided. For example,without being limited by a particular theory, mGluR5 modulators may beeffective in treating gastrointestinal disorders in human. See, e.g.,Jaeschke, G., et al., Expert Opin. Ther. Pat. 2008, 18, 123; Bolea C.,et al., WO 2004/78728 A1.

In some embodiments, a method of treating, preventing, and/or managingall categories of pain (including but not limited to: pain described interms of stimulus or nerve response; somatic pain (normal nerve responseto a noxious stimulus); neuropathic pain (abnormal response of a injuredor altered sensory pathway often without clear noxious input, andincluding chemotherapy-induced neuropathy, diabetic peripheralneuropathic pain, HIV/AIDS peripheral neuropathy, neuropathic cancerpain, and post-herpetic neuralgia); abdominal pain; acute thermalhyperalgesia; allodynia; burns; causalgia; central pain; complexregional pain syndrome (CRPS); dental pain; dual mechanism pain;dysesthesia; ear ache; episiotomy pain; eye pain; fibromyalgia;gynecological pain including dysmeorrhoea; headache (including acute andchronic tension headache and cluster headache); heart pain;hyperalgesia; hyperesthesia; hyperpathia; itching conditions includingcontact dermatitis, pruritis, and itch due to atopic dermatitis andhemodialysis; labor pain; low back pain; mechanical allodynia; mixedetiology pain; musculo-skeletal pain including that following physicaltrauma; neck pain; orofacial pain; pain associated with cystitis; paincause by convulsion; pain resulting from dysfunction of the nervoussystem (i.e., organic pain states that share clinical features ofneuropathic pain and possibly common pathophysiology mechanism, but arenot initiated by an identifiable lesion in any part of the nervoussystem); pain that is a symptom or a result of a disease state orsyndrome (such as AIDS pain, ankylosing spondylitis; arthritis pain,cancer pain, cardiac ischaemia, carpal tunnel syndrome, diabeticperipheral neuropathic pain, episcleritis, gout, inflammation, irritablebowel syndrome, migraine, neuropathy arising from chronic alcohol use,repetitive motion injury, pain from autoimmune diseases, pain fromrespiratory diseases, scar pain, sciatica; scleritis; and trigeminalneuralgia); pain that is categorized in terms of its severity (mild,moderate, or severe pain); pain that is categorized temporally (chronicpain and acute pain); phantom limb pain; post-surgical pain; reflexsympathetic dystrophy; sinus pain; and visceral pain) comprisingadministering to a subject in need thereof an effective amount of acompound as disclosed herein is provided. See e.g., Jaeschke, G., etal., Expert Opin. Ther. Pat. 2008, 18, 123; Cosford, N. D. P., et al.,WO 2003/51315 A2.

In some embodiments, a method of treating, preventing, and/or managingmigraine, comprising administering to a subject in need thereof aneffective amount of a compound as disclosed herein is provided Forexample, without being limited by a particular theory, mGluR5 modulatorsmay be effective in the treatment and prevention of migraine in human,and may have comparable efficacy to triptans in treating migraine. See,e.g., Jaeschke, G., et al., Expert Opin. Ther. Pat. 2008, 18, 123.

In some embodiments, a method of treating, preventing, and/or managingsubstance abuse disorder or eating disorder (including but not limitedto the abuse of or addiction to canabbis, cocaine, morphine, opioid,nicotine, or alcohol; substance-abuse related disorders and addictivebehaviors (including substance-induced delirium); tolerance, dependenceor withdrawal from substances including alcohol, amphetamines,anxiolytics, cannabis, cocaine, hallucinogens, hypnotics, inhalants,nicotine, opioids, phencyclidine, or sedatives; anorexia nervosa; bingeeating; bulimia nervosa; cachexia; compulsive eating disorder; emesis;and obesity) comprising administering to a subject in need thereof aneffective amount of a compound as disclosed herein is provided. Seee.g., Jaeschke, G., et al., Expert Opin. Ther. Pat. 2008, 18, 123.

In other embodiments, a method of treating, preventing, and/or managinga disorder of the genitourinary tract or a sexual disorder (includingbut limited to: lower urinary tract disorder; overactive bladder;urinary incontinence including without limitation involuntary voiding ofurine, dribbling or leakage of urine, stress urinary incontinence (SUI),urge incontinence, urinary exertional incontinence, reflex incontinence,passive incontinence, and overflow incontinence; and sexual dysfunction,in men or women, including without limitation sexual dysfunction causedby psychological and/or physiological factors, erectile dysfunction,premature ejaculation, vaginal dryness, lack of sexual excitement,inability to obtain orgasm, and psychosexual dysfunction, includingwithout limitation, inhibited sexual desire, inhibited sexualexcitement, inhibited female orgasm, inhibited male orgasm, functionaldyspareunia, functional vaginismus, and atypical psychosexualdysfunction), comprising administering to a subject in need thereof aneffective amount of a compound as disclosed herein is provided.

In other embodiments, a method of treating, preventing, and/or managingcancer, including but not limited to, oral cancer and glioneuronalcancer, comprising administering to a subject in need thereof aneffective amount of a compound as disclosed herein is provided.

In some embodiments, a compound as disclosed herein is active in atleast one model, which can be used to measure the activity of thecompounds and estimate their efficacy in treating a disorder related tomGluR5. For example, when the model is for depression (e.g., meanimmobility), the compounds are active when they inhibit mean immobilityof a test subject by about 5%, about 10%, about 20%, about 30%, about40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%,about 99%, or more, when compared to vehicle. In some embodiments, thecompound as disclosed herein produce a similar disparity in measuredendpoint between treated animals and animals administered vehicle.

Other exemplary diseases and conditions that may be treated, prevented,and/or managed using the methods, compounds as disclosed herein andcompositions thereof, include, but are not limited to: metabolicdiseases including diabetes and pulmonary/respiratory diseases includingasthma, chronic obstructive pulmonary disease (COPD), chronicbronchitis, cystic fibrosis, and emphysema.

In one embodiment, the compounds described herein treat, prevent, and/ormanage a neurological disorder, without causing addiction to saidcompounds. Any suitable route of administration can be employed forproviding the patient with a therapeutically or prophylacticallyeffective dose of an active ingredient. For example, oral, mucosal(e.g., nasal, sublingual, buccal, rectal, vaginal), parenteral (e.g.,intravenous, intramuscular), transdermal, and subcutaneous routes can beemployed. Exemplary routes of administration include oral, transdermal,and mucosal. Suitable dosage forms for such routes include, but are notlimited to, transdermal patches, ophthalmic solutions, sprays, andaerosols. Transdermal compositions can also take the form of creams,lotions, and/or emulsions, which can be included in an appropriateadhesive for application to the skin or can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose. An exemplary transdermal dosage form is a “reservoir type”or “matrix type” patch, which is applied to the skin and worn for aspecific period of time to permit the penetration of a desired amount ofactive ingredient. The patch can be replaced with a fresh patch whennecessary to provide constant administration of the active ingredient tothe patient.

The amount to be administered to a patient to treat, prevent, and/ormanage the disorders described herein will depend upon a variety offactors including the activity of the particular compound employed, orthe ester, salt or amide thereof, the route of administration, the timeof administration, the rate of excretion or metabolism of the particularcompound being employed, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount required. For example, thephysician or veterinarian could start doses of the compounds employed atlevels lower than that required in order to achieve the desiredtherapeutic effect and gradually increase the dosage until the desiredeffect is achieved.

In general, a suitable daily dose of a compound set forth herein will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic or prophylactic effect. Such an effective dosewill generally depend upon the factors described above. Generally, oral,intravenous, intracerebroventricular, and subcutaneous doses of thecompounds set forth herein for a patient will range from about 0.005 mgper kilogram to about 5 mg per kilogram of body weight per day. In oneembodiment, the oral dose of a compound set forth herein will range fromabout 10 mg to about 300 mg per day. In another embodiment, the oraldose of a compound set forth herein will range from about 20 mg to about250 mg per day. In another embodiment, the oral dose of a compound setforth herein will range from about 100 mg to about 300 mg per day. Inanother embodiment, the oral dose of a compound set forth herein willrange from about 10 mg to about 100 mg per day. In another embodiment,the oral dose of a compound set forth herein will range from about 25 mgto about 50 mg per day. In another embodiment, the oral dose of acompound set forth herein will range from about 50 mg to about 200 mgper day. Each of the above-recited dosage ranges may be formulated as asingle or multiple unit dosage formulations.

In some embodiments, the compounds disclosed herein may be used incombination with one or more second active agents to treat, prevent,and/or manage disorders described herein.

Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound set forth herein, or apharmaceutically acceptable salt, solvate, stereoisomer, clathrate, orprodrug thereof. Pharmaceutical compositions and dosage forms canfurther comprise one or more excipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are also disclosed herein.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another and will be readily apparent to those skilled in the art.See, e.g., Remington's Pharmaceutical Sciences, 18th Ed., MackPublishing, Easton Pa. (1990).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or di-saccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are preferably anhydrous if substantialcontact with moisture and/or humidity during manufacturing, packaging,and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In one embodiment, dosage forms comprise a compound setforth herein in an amount of from about 0.10 to about 500 mg. In otherembodiments, dosage forms comprise a compound set forth herein in anamount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100,150, 200, 250, 300, 350, 400, 450, or 500 mg.

In other embodiments, dosage forms comprise the second active ingredientin an amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated or managed,and the amount(s) of a compound set forth herein, and any optionaladditional active agents concurrently administered to the patient.

Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington's TheScience and Practice of Pharmacy, 21st Ed., Lippincott Williams &Wilkins (2005).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or non-aqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. In oneembodiment, pharmaceutical compositions comprise from about 0.5 to about15 weight percent of disintegrant, or from about 1 to about 5 weightpercent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a compound setforth herein, and optional excipients, such as anhydrous lactose,microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,colloidal anhydrous silica, and gelatin.

Controlled Release Dosage Forms

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. In one embodiment, provided aresingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled-release.

In one embodiment, controlled-release pharmaceutical products improvedrug therapy over that achieved by their non-controlled counterparts. Inanother embodiment, the use of a controlled-release preparation inmedical treatment is characterized by a minimum of drug substance beingemployed to cure or control the condition in a minimum amount of time.Advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

In another embodiment, the controlled-release formulations are designedto initially release an amount of drug (active ingredient) that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release of other amounts of drug to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In one embodiment, in order to maintain a constant level of drug in thebody, the drug can be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient. Examples of parenteraldosage forms include, but are not limited to, solutions ready forinjection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound set forth herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16thand 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, prodrugs, clathrates, orstereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition.

Kits

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound set forthherein. Kits can further comprise one or more second active ingredientsas described herein, or a pharmacologically active mutant or derivativethereof, or a combination thereof.

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

I. EXAMPLES

Certain embodiments are illustrated by the following non-limitingexamples.

A. Synthesis of Compounds

In the examples below, unless otherwise indicated, all temperatures areset forth in degrees Celsius and all parts and percentages are byweight. Reagents may be purchased from commercial suppliers, such asSigma-Aldrich Chemical Company, and may be used without furtherpurification unless otherwise indicated. Reagents may also be preparedfollowing standard literature procedures known to those skilled in theart. Solvents may be purchased from Aldrich in Sure-Seal bottles andused as received. All solvents may be purified using standard methodsknown to those skilled in the art, unless otherwise indicated.

The reactions set forth below were done generally at ambienttemperature, unless otherwise indicated. The reaction flasks were fittedwith rubber septa for introduction of substrates and reagents viasyringe. Analytical thin layer chromatography (TLC) was performed usingglass-backed silica gel pre-coated plates (Merck Art 5719) and elutedwith appropriate solvent ratios (v/v). Reactions were assayed by TLC orLCMS, and terminated as judged by the consumption of starting material.Visualization of the TLC plates was done with UV light (254 wavelength)or with an appropriate TLC visualizing solvent, such as basic aqueousKMnO₄ solution activated with heat. Flash column chromatography (See,e.g., Still et al., J. Org. Chem., 43: 2923 (1978)) was performed usingsilica gel 60 (Merck Art 9385) or various MPLC systems.

The compound structures in the examples below were confirmed by one ormore of the following methods: proton magnetic resonance spectroscopy,mass spectroscopy, and melting point. Proton magnetic resonance (¹H NMR)spectra were determined using an NMR spectrometer operating at 400 MHzfield strength. Chemical shifts are reported in the form of delta (δ)values given in parts per million (ppm) relative to an internalstandard, such as tetramethylsilane (TMS). Alternatively, ¹H NMR spectrawere referenced to signals from residual protons in deuterated solventsas follows: CDCl₃=7.25 ppm; DMSO-d⁶=2.49 ppm; C₆D₆=7.16 ppm; CD₃OD=3.30ppm. Peak multiplicities are designated as follows: s, singlet; d,doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets;q, quartet; br, broadened; and m, multiplet. Coupling constants aregiven in Hertz (Hz). Mass spectra (MS) data were obtained using a massspectrometer with APCI or ESI ionization.

As used herein, and unless otherwise specified, “4 Å MS” means 4angstrom molecular sieves, “Ac” means acetyl, “aq” means aqueous,“BINAP” means 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, “cat.” meanscatalytic, “DCE” means 1,2-dichloroethane, “DAST” means(diethylamino)sulfur trifluoride (Et₂NSF₃), “DCM” means dichloromethane,“Dess-Martin reagent” means1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (alsocalled DMP), “DIEA” means diisopropylethylamine, “DMAP” means4-dimethylaminopyridine, “DME” means 1,2-dimethoxyethane, “DMF” meansdimethylformamide, “DMF-DMA” means N,N-dimethylformamide dimethylacetal,“DMSO” means dimethyl sulfoxide, “EDCI” meansN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, “equiv”and “eq” mean equivalent(s), “Et” means ethyl, “EtOAc” means ethylacetate, “EtOH” means ethanol, “Fmoc” means 9-fluorenylmethoxycarbonyl,“h” or “hr” means hour(s), “HOBt” means hydroxybenzotriazole, “LDA”means lithium diisopropylamide, “m-CPBA” means 3-chloro-perbenzoic acid,“Me” means methyl, “MeCN” means acetonitrile, “MeOH” means methanol,“Ms” means mesyl (CH₃SO₂—), “min” means minute(s), “NMP” meansN-methylpyrrolidone, “PE” means petroleum ether, “PPA” meanspolyphosphoric acid, “RT” or “rt” means room temperature, “Selectfluor”means 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.0]octaneditetrafluoroborate, “TBDMSCl” means tert-butyldimethylsilyl chloride,“t-BuOH” means tert-butanol, “t-BuONa” means sodium tert-butoxide,“TBTU” means 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate, “TEA” means triethylamine, “Tebbe Reagent” meansmeansμ-chloro[di(cyclopenta-2,4-dien-1-yl)]dimethyl(μ-methylene)titaniumaluminum,“TFA” means trifluoroacetic acid, “THF” means tetrahydrofuran, “TMSI”means iodotrimethylsilane, “o-Tol” means o-tolyl (2-CH₃C₆H₄), “m-Tol”means p-tolyl (4-CH₃C₆H₄), “Ts” means tosyl (p-CH₃C₆H₄SO₂), and“Xantphos” means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. Forthose compounds containing basic nitrogen center(s), its HCl salt wasprepared by treating the freebase with excess HCl etherate solution.

mGluR5 PAM EC₅₀ values: +++++<10 nM; ++++ is between 10 and 30 nM; +++is between 30 and 100 nM; ++ is between 100 and 300 nM; + is between 300and 1,000 nM. Fold shift at 10 μM: +++>3; ++ is between 2.0 and 2.9; +is between 1.5 and 1.9.

Example 1.1 Synthesis of 7-((4-fluorophenyl)ethynyl)quinazolin-4(3H)-one

A flask was charged with 7-bromoquinazolin-4(3H)-one (60 mg, 0.27 mmol,1 equiv), 1-ethynyl-4-fluorobenzene (81 mg, 0.675 mmol, 2.5 equiv),Pd(OAc)₂ (12.2 mg, 0.054 mmol, 0.2 equiv), PPh₃ (63.7 mg, 0.24 mmol, 0.9equiv), CuI (10.3 mg, 0.054 mmol, 0.2 equiv), Et₃N (0.3 mL) and DMF (6mL). A vacuum was applied and the reaction mixture was back filled withnitrogen three times. The mixture was stirred at 70° C. for 3.5 hours.After it was cooled to room temperature, the reaction mixture wasdiluted with H₂O and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine and dried over anhydroussodium sulfate, then concentrated under reduced pressure and purified bycolumn chromatography to give the desired product. MS (ESI): 265 (MH⁺);¹H NMR (300 MHz, DMSO-d⁶) δ 12.38-12.33 (m, 1H), 8.13 (s, 2H), 7.81 (s,1H), 7.69-7.54 (m, 3H), 7.39-7.29 (m, 2H).

Example 1.2 Synthesis of 7-((3-fluorophenyl)ethynyl)quinazolin-4(3H)-one

The title compound was prepared from 7-bromoquinazolin-4(3H)-one and1-ethynyl-3-fluorobenzene according to the experimental procedure asdescribed in Example 1.1. MS (ESI): 265 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶)δ 12.37 (s, 1H), 8.14 (s, 2H), 7.83 (s, 1H), 7.68-7.64 (m, 1H),7.53-7.49 (m, 3H), 7.36-7.33 (m, 1H). mGluR5 PAM EC₅₀: +.

Example 1.3 Synthesis of 3-methyl-7-(phenylethynyl)quinazolin-4(3H)-one

Example 1.3a Synthesis of 7-bromo-3-methylquinazolin-4(3H)-one

A solution of 4-bromo-2-nitrobenzoic acid (1 g, 4.1 mmol) and InCl₃(0.88 g, 4 mmol) in N-methylformamide (6 mL, 100 mmol) was stirred atreflux overnight (ca. 18 h). After it was cooled to room temperature,the mixture was diluted with H₂O (30 mL) and extracted with ethylacetate (3×30 mL). The combined organic layers were washed with brine,and dried over Na₂SO₄. After filtration and concentration, the crudeproduct was purified by column chromatography to give the desiredproduct (0.5 g). MS (ESI): 239 (MH⁺).

Example 1.3b Synthesis of 3-methyl-7-(phenylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 261 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.31-8.29 (d, J=8.25 Hz, 1H), 8.08 (s, 1H), 7.87 (s, 1H),7.65-7.58 (m, 3H), 7.41-7.39 (m, 3H), 3.61 (s, 3H). mGluR5 PAM EC₅₀: ++.

Example 1.4 Synthesis of7-((4-ethylphenyl)ethynyl)-3-methylquinazolin-4(3H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 289 (MH⁺); ¹H NMR (300 MHz,DMSO-d⁶) δ 8.41 (s, 1H), 8.17-8.14 (d, J=8.22 Hz, 1H), 7.80-7.79 (d,J=1.05 Hz, 1H), 7.66-7.23 (dd, J=8.25, 1.44 Hz, 1H), 7.56-7.53 (d,J=8.01 Hz, 2H), 7.32-7.29 (d, J=8.10 Hz, 2H), 3.50 (s, 3H), 2.69-2.62(m, 2H), 1.22-1.17 (t, J=7.56 Hz, 3H).

Example 1.5 Synthesis of3-methyl-7-(thiazol-2-ylethenyl)quinazolin-4(3H)-one

Example 1.5a Synthesis of3-methyl-7-((trimethylsilyl)ethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.1d. MS (ESI): 257 (MH⁺).

Example 1.5b Synthesis of 7-ethynyl-3-methylquinazolin-4(3H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.1e. MS (ESI): 185 (MH⁺).

Example 1.5c Synthesis of3-methyl-7-(thiazol-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 268 (MH⁺); ¹H NMR (300 MHz,CD₃OD) δ 8.37 (s, 1H), 8.32-8.30 (d, J=8.40 Hz, 1H), 7.98-7.93 (m, 2H),7.81-7.80 (d, J=3.30 Hz, 1H), 7.77-7.74 (d, J=8.25 Hz, 1H), 3.62 (m,3H). mGluR5 PAM EC₅₀: +.

Example 1.6 Synthesis of7-((4-fluorophenyl)ethynyl)-3-propylquinazolin-4(3H)-one

Example 1.6a Synthesis of 7-bromo-3-propylquinazolin-4(3H)-one

To a mixture of 7-bromoquinazolin-4(3H)-one (0.2 g, 0.89 mmol) and DMF(20 mL) was added sodium hydride (85 mg, 3.5 mmol) in portions. Thereaction mixture was stirred at room temperature for 15 min1-iodopropane (0.18 g, 1.1 mmol) was added dropwise. After stirring for30 min., the reaction mixture was quenched with water (20 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over Na₂SO₄. After filtration and concentration, the residue waspurified by silica gel chromatography to give the desired product. MS(ESI): 267, 269 (MH⁺).

Example 1.6b Synthesis of7((4-fluorophenyl)ethynyl)-3-propylquinazolin-4(3H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 307 (M+H⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.31-8.28 (d, J=8.22 Hz, 1H), 8.05 (s, 1H), 7.85-7.84 (d,J=1.14 Hz, 1H), 7.62-7.55 (m, 3H), 7.12-7.07 (t, J=8.72 Hz, 2H),4.00-3.96 (t, J=7.23 Hz, 2H), 1.89-1.82 (m, 2H), 1.05-1.00 (t, J=7.43Hz, 3H). mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM: ++.

Example 1.7 Synthesis of7-((3-fluorophenyl)ethynyl)-3-propylquinazolin-4(3H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.6a and Example 1.1. MS (ESI): 307 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.31-8.29 (d, J=8.25 Hz, 1H), 8.05 (s, 1H), 7.88(s, 1H), 7.64-7.60 (d, J=8.27 Hz, 1H), 7.38-7.30 (m, 3H), 7.14-7.07 (m,1H), 4.01-3.96 (t, J=7.20 Hz, 2H), 1.92-1.80 (m, 2H), 1.05-1.00 (t,J=7.41 Hz, 3H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: +++.

Example 1.8 Synthesis of 3-(cyclopropylmethyl)-7-((3-fluorophenyl)ethynyl) quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.6a and Example 1.1. MS (ESI): 319 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.32-8.29 (d, J=8.31 Hz, 1H), 8.14 (s, 1H), 7.87 (s,1H), 7.64-7.61 (d, J=8.22 Hz, 1H), 7.38-7.30 (m, 3H), 7.14-7.08 (m, 1H),3.90-3.88 (d, J=7.17 Hz, 2H), 1.34-1.27 (m, 1H), 0.73-0.64 (m, 2H),0.48-0.44 (m, 2H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.

Example 1.9 Synthesis of 3-(cyclopropylmethyl)-7-((4-fluorophenyl)ethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.6a and Example 1.1. MS (ESI): 319 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.31-8.28 (d, J=8.75 Hz, 1H), 8.14 (s, 1H), 7.85 (s,1H), 7.63-7.56 (m, 3H), 7.13-7.07 (t, J=8.67 Hz, 2H), 3.90-3.88 (d,J=7.17 Hz, 2H), 1.36-1.27 (m, 1H), 0.70-0.64 (m, 2H), 0.48-0.44 (m, 2H).mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM: +++.

Example 1.10 Synthesis of3-cyclopentyl-7-((4-fluorophenyl)ethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.6a and Example 1.1. MS (ESI): 333 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.30-8.27 (d, J=8.28 Hz, 1H), 8.14 (s, 1H), 7.84 (s,1H), 7.62-7.56 (m, 3H), 7.13-7.17 (m, 2H), 5.22-5.17 (m, 1H), 2.27-2.22(m, 2H), 1.96-1.78 (m, 6H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM:++.

Example 1.11 Synthesis of3-cyclopentyl-7-((3-fluorophenyl)ethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.6a and Example 1.1. MS (ESI): 333 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.31-8.28 (d, J=8.31 Hz, 1H), 8.15 (s, 1H), 7.85 (s,1H), 7.63-7.60 (d, J=8.28 Hz, 1H), 7.38-7.30 (m, 3H), 7.14-7.07 (m, 1H),5.22-5.15 (m, 1H), 2.31-2.23 (m, 2H), 1.96-1.76 (m, 6H). mGluR5 PAMEC₅₀: ++++. Fold shift at 10 μM: +.

Example 1.12 Synthesis of7-((4-fluorophenyl)ethynyl)-3-(2-methoxyethyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.6a and Example 1.1. MS (ESI): 323 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.30-8.27 (d, J=8.10 Hz, 1H), 8.12 (s, 1H), 7.85 (s,1H), 7.62-7.56 (m, 3H), 7.12-7.07 (m, 2H), 4.22-4.18 (t, J=9.66 Hz, 2H),3.71-3.68 (t, J=4.98 Hz, 2H), 3.35 (s, 3H). mGluR5 PAM EC₅₀: +++. Foldshift at 10 μM: +++.

Example 1.13 Synthesis of7-((4-fluorophenyl)ethynyl)-3-((tetrahydrofuran-2-yl)methyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.6a and Example 1.1. MS (ESI): 349 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.29-8.27 (d, J=8.28 Hz, 1H), 8.18 (s, 1H), 7.85 (s,1H), 7.62-7.55 (m, 3H), 7.12-7.06 (m, 2H), 4.40-4.35 (d, J=13.79 Hz,1H), 4.28-4.20 (m, 1H), 3.93-3.74 (m, 3H), 2.18-2.07 (m, 1H), 1.97-1.87(m, 2H), 1.64-1.56 (m, 1H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM:++.

Example 1.14 Synthesis of7-((4-fluorophenyl)ethynyl)-3-(furan-2-ylmethyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.6a and Example 1.1. MS (ESI): 345 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.30-8.27 (d, J=8.67 Hz, 1H), 8.20 (s, 1H), 7.85 (s,1H), 7.79-7.73 (m, 3H), 7.41-7.33 (m, 1H), 7.12-7.06 (t, J=8.69 Hz, 2H),6.50 (s, 1H), 6.37 (s, 1H), 5.20 (s, 2H). mGluR5 PAM EC₅₀: +. Fold shiftat 10 μM: +++.

Example 1.15 and Example 1.16 Separation of racemic7-((4-fluorophenyl)ethynyl)-3-((tetrahydrofuran-2-yl)methyl)quinazolin-4(3H)-oneinto(S)-7-((4-fluorophenyl)ethynyl)-3-((tetrahydrofuran-2-yl)methyl)quinazolin-4(3H)-oneand(R)-7-((4-fluorophenyl)ethynyl)-3-((tetrahydrofuran-2-yl)methyl)quinazolin-4(3H)-one

Racemic7-((4-fluorophenyl)ethynyl)-3-((tetrahydrofuran-2-yl)methyl)quinazolin-4(3H)-onewas separated into the corresponding two single enantiomer compounds(S)-7-((4-fluorophenyl)ethynyl)-3-((tetrahydrofuran-2-yl)methyl)quinazolin-4(3H)-oneand(R)-7-((4-fluorophenyl)ethynyl)-3-((tetrahydrofuran-2-yl)methyl)quinazolin-4(3H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 3.0×25.0 cm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was ethanol with 0.1% isopropylamine.Isocratic Method: 55% Co-solvent at 80 mL/min System Pressure: 120 bar.Column Temperature 25° C.

Faster moving enantiomer (fraction 1): Retention time=2.31 min 100% ee.mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: ++.Slower moving enantiomer (fraction 2): Retention time=3.59 min 99.2% ee.mGluR5 PAM EC₅₀: ++.

Example 1.17 Synthesis of3-(2-methoxyethyl)-7-(pyridin-4-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.6a and Example 1.1. MS (ESI): 306 (MH⁺). mGluR5PAM EC₅₀: ++. Fold shift at 10 μM: ++.

Example 1.18 Synthesis of3-(2-methoxyethyl)-7-(pyridin-3-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.6a and Example 1.1. MS (ESI): 306 (MH⁺).

Example 1.19 Synthesis of3-(sec-butyl)-7-((3-fluorophenyl)ethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.6a and Example 1.1. MS (ESI): 321 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.32-8.29 (d, J=8.37 Hz, 1H), 8.08 (s, 1H), 7.87 (s,1H), 7.64-7.61 (d, J=8.28 Hz, 1H), 7.39-7.35 (m, 2H), 7.28 (s, 1H),7.14-7.08 (m, 1H), 5.01-4.94 (m, 1H), 1.92-1.82 (m, 2H), 1.51-1.48 (d,J=6.96 Hz, 3H), 0.99-0.94 (t, J=7.5 Hz, 3H). mGluR5 PAM EC₅₀: +++++.Fold shift at 10 μM: ++.

Example 1.20 Synthesis of7-((3-fluorophenyl)ethynyl)-3-isobutylquinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.6a and Example 1.1. MS (ESI): 321 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.31-8.29 (d, J=8.31 Hz, 1H), 8.02 (s, 1H), 7.86 (s,1H), 7.64-7.61 (d, J=8.27 Hz, 1H), 7.38-7.35 (m, 2H), 7.32-7.28 (m, 1H),7.14-7.07 (m, 1H), 3.84-3.81 (d, J=7.35 Hz, 2H), 2.28-2.19 (m, 1H),1.03-1.00 (d, J=8.69 Hz, 6H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM:++.

Example 1.21 Synthesis of7-((3-fluorophenyl)ethynyl)-3-((1-methylpyrrolidin-2-yl)methyl)quinazolin-4(3H)-one

Example 1.21a Synthesis of tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate(1.00 g, 4.97 mmol, 1.0 equiv) and Et₃N (1.06 g, 10.5 mmol, 2.1 equiv)in DCM (15 mL) was added dropwise MsCl (0.85 g, 7.40 mmol, 1.5 equiv) at0° C. Then the reaction mixture was stirred at room temperature for 3 h.After the mixture was washed with brine, the organic layer wasseparated, dried over Na₂SO₄, filtered, and concentrated to give 1.8 gof the crude product, which was used for the nest step without furtherpurification.

Example 1.21b Synthesis of tert-butyl2-((7-((3-fluorophenyl)ethynyl)-4-oxoquinazolin-3(4H)-yl)methyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (0.86 g, 3.42mmol, 5.4 equiv) and 7-((3-fluorophenyl)ethynyl)quinazolin-4(3H)-one(0.15 g, 0.57 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added KOH (0.38g, 6.98 mmol, 12 equiv). The reaction mixture was stirred at refluxovernight. After it was cooled to room temperature, the reaction mixturewas diluted with saturated NaCl and extracted with ethyl acetate (3×50mL). The combined organic layers were dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by silica gelchromatography to give 0.74 g of the desired product. MS (ESI): 448(MH⁺).

Example 1.21c Synthesis of7-((3-fluorophenyl)ethynyl)-3-(pyrrolidin-2-ylmethyl)quinazolin-4(3H)-one

A mixture of tert-butyl2-474(3-fluorophenyl)ethynyl)-4-oxoquinazolin-3(4H)-yl)methyl)pyrrolidine-1-carboxylate(0.74 g) and TFA (4 mL) in dichloromethane (4 mL) was stirred at roomtemperature for 2.5 h. Then the reaction mixture was adjusted pH to 8-9with saturated NaHCO₃ and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated to givethe crude product (0.4 g), which was used for the next step withoutfurther purification. MS (ESI): 348 (MH⁺).

Example 1.21d Synthesis of the HCl salt of7-((3-fluorophenyl)ethynyl)-3-((1-methylpyrrolidin-2-yl)methyl)quinazolin-4(3H)-one

To a solution of7-((3-fluorophenyl)ethynyl)-3-(pyrrolidin-2-ylmethyl)quinazolin-4(3H)-one(0.4 g, 1.15 mmol, 1 equiv), 37% HCHO (0.7 mL, 2.3 mmol, 2 equiv) andHOAc (1 d) in MeOH (20 mL) was added NaCNBH₃ in portions. After thereaction mixture was stirred at room temperature for 1 h, the solventwas removed, diluted with saturated NaHCO₃ and extracted with ethylacetate (3×50 mL). The combined organic layers were dried over Na₂SO₄.After filtration and concentration, the residue was purified by silicagel chromatography to give 42 mg of the desired product. The product wasthen converted to the corresponding HCl salt. MS (ESI): 362 (MH⁺).

¹H NMR (300 MHz, CD₃OD) δ 8.20 (s, 1H), 8.36-8.33 (d, J=8.4 Hz, 1H),7.91 (s, 1H), 7.80-7.77 (d, J=9.0 Hz, 1H), 7.51-7.42 (m, 2H), 7.38-7.35(m, 1H), 7.25-7.18 (m, 1H), 4.86-4.54 (m, 2H), 3.89-3.79 (m, 2H),3.28-3.22 (m, 1H), 3.12 (s, 3H), 2.47-2.36 (m, 1H), 2.23-2.06 (m, 2H),2.02-1.93 (m, 1H). mGluR5 PAM EC₅₀: ++.

Example 2.1 Synthesis of7-((3-fluorophenyl)ethynyl)-2-(2-methoxyethyl)-3-methylquinazolin-4(3H)-one

Example 2.1a Synthesis of 2-amino-4-bromo-N-methylbenzamide

To a mixture of 2-amino-4-bromobenzoic acid (5.0 g, 23.1 mmol) anddioxane (50 mL) was added triphosgene (2.3 g, 7.75 mmol). The reactionmixture was heated to reflux and stirred for 4 h. Methylamine (40% inwater, 2 mL, 23.1 mmol) was added dropwise after the mixture was cooledto room temperature. After stirring for 30 min, the solution wasevaporated under reduced pressure and the residue was redissolved in DCMwhich was washed with sat. NaHCO₃ aqueous solution, dried over Na₂SO₄,filtered, and evaporated to give 4.6 g of the target compound. MS (ESI):229, 231 (MH⁺).

Example 2.1b Synthesis of4-bromo-2-(3-methoxypropanamido)-N-methylbenzamide

To a mixture of 3-methoxypropanoic acid (0.25 mL, 2.62 mmol), DMAP (0.64g, 5.24 mmol) and dry DCM (5 mL) was added methanesulfonyl chloride(0.22 mL, 2.88 mmol) dropwise at 0° C. under nitrogen atmosphere.2-Amino-4-bromo-N-methylbenzamide (0.3 g, 1.31 mmol) was added afterstirring for 1 h, and the temperature was allowed to rise to roomtemperature slowly. The reaction mixture was quenched with sat. NH₄Clsolution after 3 h and extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with NaHCO₃, dried over Na₂SO₄,filtered, and evaporated to give 0.39 g of the target compound. MS(ESI): 315, 317 (MH⁺).

Example 2.1c Synthesis of7-bromo-2-(2-methoxyethyl)-3-methylquinazolin-4(3H)-one

The mixture of 4-bromo-2-(3-methoxypropanamido)-N-methylbenzamide (0.05g, 0.159 mmol), 2.5 N NaOH (1 mL) and dioxane (1 mL) was stirred for 3 hat room temperature, then diluted with water, and extracted with ethylacetate (3×10 mL). The combined organic layers were washed with brine(3×10 mL), dried over Na₂SO₄, filtered, and evaporated to give 59 mg ofthe target compound. MS (ESI): 297, 299 (MH⁺).

Example 2.1d Synthesis of7-((3-fluorophenyl)ethynyl)-2-(2-methoxyethyl)-3-methylquinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.1. MS (ESI): 337 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ8.26-8.23 (d, J=8.25 Hz, 1H), 7.81 (s, 1H), 7.57-7.54 (d, J=8.30 Hz,1H), 7.38-7.34 (m, 2H), 7.27-7.26 (m, 1H), 7.15-7.07 (m, 1H), 3.98-3.93(t, J=6.60 Hz, 2H), 3.67 (s, 3H), 3.43 (s, 3H), 3.15-3.10 (t, J=6.69 Hz,2H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: +.

Example 2.2 Synthesis of7-((3-fluorophenyl)ethynyl)-3-methyl-2-(tetrahydrofuran-3-yl)quinazolin-4(3H)-one

Example 2.2a Synthesis of7-bromo-3-methyl-2-(tetrahydrofuran-3-yl)quinazolin-4(3H)-one

The mixture of 2-amino-4-bromobenzoic acid (349 mg, 1.62 mmol),N-methyltetrahydrofuran-3-carboxamide (190 mg, 1.47 mmol), SOCl₂ (0.13mL, 1.76 mmol) and toluene (10 mL) was stirred at 80° C. for 5 h, andNa₂CO₃ aqueous solution was added after the mixture was cooled to roomtemperature. The water layer was extracted with ethyl acetate (3×10 mL)and the combined organic layers were dried over Na₂SO₄, filtered, andevaporated to give the desired product, which was directly used for thenext step. MS (ESI): 309, 311 (MH⁺).

Example 2.2b Synthesis of7-((3-fluorophenyl)ethynyl)-3-methyl-2-(tetrahydrofuran-3-yl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.1. MS (ESI): 349 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ8.34-8.32 (d, J=8.16 Hz, 1H), 7.77 (s, 1H), 7.62-7.56 (d, J=8.16 Hz,1H), 7.38-7.34 (m, 2H), 7.27-7.24 (m, 1H), 7.15-7.07 (m, 1H), 4.25-4.22(d, J=6.99 Hz, 2H), 4.13-3.97 (m, 2H), 3.71-3.61 (m, 4H), 2.54-2.46 (m,1H), 2.43-2.31 (m, 1H). mGluR5 PAM EC₅₀: +.

Example 2.3 Synthesis of7-((3-fluorophenyl)ethynyl)-3-methyl-2-(tetrahydrofuran-2-yl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.2a and Example 1.1. MS (ESI): 349 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.27-8.25 (d, J=8.25 Hz, 1H), 7.88 (s, 1H), 7.60-7.56(d, J=8.25 Hz, 1H), 7.38-7.32 (m, 2H), 7.27-7.25 (m, 1H), 7.13-7.07 (m,1H), 5.11-5.07 (m, 1H), 4.06-3.94 (m, 2H), 3.76 (s, 3H), 2.82-2.76 (m,1H), 2.24-2.18 (m, 2H), 2.11-2.02 (m, 1H). mGluR5 PAM EC₅₀: +.

Example 2.4 Synthesis of7-((3-fluorophenyl)ethynyl)-3-methyl-2-(1-methylpyrrolidin-2-yl)quinazolin-4(3H)-one

Example 2.4a Synthesis of tert-butyl2-(5-bromo-2-(methylcarbamoyl)phenylcarbamoyl)pyrrolidine-1-carboxylate

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b. MS (ESI): 426, 428 (MH⁺).

Example 2.4b Synthesis of7-bromo-3-methyl-2-(pyrrolidin-2-yl)quinazolin-4(3H)-one

The mixture of tert-butyl2-(5-bromo-2-(methylcarbamoyl)phenylcarbamoyl)pyrrolidine-1-carboxylate(0.2 g, 0.47 mmol), hexamethyldisilazane (0.39 mL, 1.88 mmol), I₂ (0.24g, 0.94 mmol), and DCM (10 mL) was refluxed for 5 h under nitrogenatmosphere. Na₂S₂O₃ aqueous solution was added to quench the reactionfollowed by cooling to room temperature. The organic layer was separatedand the water layer was extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and evaporated to give the desired product, which was directlyused for the next step. MS (ESI): 308, 310 (MH⁺).

Example 2.4c Synthesis of7-bromo-3-methyl-2-(1-methylpyrrolidin-2-yl)-quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.21d. MS (ESI): 322, 324 (MH⁺).

Example 2.4d Synthesis of the HCl salt of7-((3-fluorophenyl)ethynyl)-3-methyl-2-(tetrahydrofuran-3-yl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.1. The mixture of7-((3-fluorophenyl)ethynyl)-3-methyl-2-(tetrahydrofuran-3-yl)quinazolin-4(3H)-oneand DCM was treated with HCl/Et₂O, filtered to give the desired HClsalt. MS (ESI): 362 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.29-8.26 (d,J=8.19 Hz, 1H), 7.95 (s, 1H), 7.74-7.71 (dd, J=8.27, 1.55 Hz, 1H),7.48-7.41 (m, 2H), 7.37-7.33 (m, 1H), 7.27-7.21 (m, 1H), 5.04-4.98 (m,1H), 3.99-3.95 (m, 1H), 3.62 (s, 3H), 3.46-3.38 (m, 1H), 3.09 (s, 3H),2.93-2.87 (m, 1H), 2.40-2.30 (m, 1H), 2.24-2.11 (m, 2H). mGluR5 PAMEC₅₀: ++. Fold shift at 10 μM: ++.

Example 2.5 Synthesis of7-((3-fluorophenyl)ethynyl)-3-methyl-2-(1-methylpyrrolidin-3-yl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.4b, Example 1.21d, and Example 1.1.MS (ESI): 362 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.23-8.21 (d, J=8.28 Hz,1H), 7.96-7.89 (dd, J=19.66, 1.26 Hz, 1H), 7.67-7.64 (d, J=8.28 Hz, 1H),7.50-7.40 (m, 2H), 7.35-7.32 (m, 1H), 7.24-7.18 (m, 1H), 4.40-4.36 (d,J=11.68 Hz, 1H), 4.24-4.03 (m, 1H), 3.87-3.82 (m, 1H), 3.70 (s, 3H),3.12 (s, 3H), 2.92-2.77 (m, 1H), 2.71-2.60 (m, 1H), 2.50-2.25 (m, 2H).

Example 2.6 Synthesis of7-((3-fluorophenyl)ethynyl)-3-methyl-2-(pyrrolidin-1-ylmethyl)quinazolin-4(3H)-one

Example 2.6a Synthesis of7-bromo-2-(chloromethyl)-3-methylquinazolin-4(3H)-one

The mixture of 2-amino-4-bromo-N-methylbenzamide (0.4 g, 1.75 mmol) and2-chloro-1,1,1-trimethoxyethane (4 mL) was stirred at 110° C. for 6 h.After the solution was evaporated under reduced pressure, ice cooledethyl acetate was used to wash the residue to give 0.25 g of the desiredproduct which was used for the next step without further purification.MS (ESI): 287, 289 (MH⁺).

Example 2.6b Synthesis of7-bromo-3-methyl-2-(pyrrolidin-1-ylmethyl)quinazolin-4(3H)-one

The mixture of 7-bromo-2-(chloromethyl)-3-methylquinazolin-4(3H)-one(125 mg, 0.43 mmol), pyrrolidine (65 mg, 0.91 mmol), K₂CO₃ (244 mg,1.768 mmol) and DMF (10 mL) was stirred at room temperature for 30 min.Then water was added and the mixture was extracted with ethyl acetate(3×10 mL). The combined organic layers were washed with brine (3×10 mL),dried over Na₂SO₄, filtered and evaporated to give 100 mg of the desiredproduct. MS (ESI): 322, 324 (MH⁺).

Example 2.6c Synthesis of the HCl salt of7-((3-fluorophenyl)ethynyl)-3-methyl-2-(pyrrolidin-1-ylmethyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 362 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.28-8.25 (d, J=8.16 Hz, 1H), 7.95 (s, 1H), 7.71-7.69 (dd, J=8.28, 1.53Hz, 1H), 7.50-7.40 (m, 2H), 7.36-7.32 (m, 1H), 7.24-7.18 (m, 1H),4.05-4.00 (m, 2H), 3.59 (s, 3H), 3.40-3.35 (m, 4H), 2.28-2.17 (m, 4H).mGluR5 PAM EC₅₀: ++.

Example 2.7 Synthesis of2-((dimethylamino)methyl)-7-((3-fluorophenyl)ethynyl)-3-methylquinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.6b and Example 1.1. MS (ESI): 336 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.28-8.25 (d, J=8.28 Hz, 1H), 7.95 (s, 1H), 7.73-7.69(d, J=8.25 Hz, 1H), 7.48-7.44 (m, 2H), 7.36-7.32 (m, 1H), 7.26-7.16 (m,1H), 4.75 (s, 2H), 3.58 (s, 3H), 3.18 (s, 6H). mGluR5 PAM EC₅₀: +++.Fold shift at 10 μM: ++.

Example 2.8 Synthesis of the HCl salt of2-(2-(dimethylamino)ethyl)-7-((3-fluorophenyl)ethynyl)-3-methylquinazolin-4(3H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.4b, Example 1.21d, and Example 1.1. Theproduct was then converted to the corresponding HCl salt. MS (ESI): 350(MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.24-8.22 (d, J=8.28 Hz, 1H), 7.97 (s,1H), 7.68-7.65 (dd, J=8.30, 1.52 Hz, 1H), 7.48-7.41 (m, 2H), 7.36-7.32(m, 1H), 7.26-7.20 (m, 1H), 3.77-3.73 (t, J=5.97 Hz, 2H), 3.67 (s, 3H),3.48-3.44 (t, J=5.91 Hz, 2H), 3.5807 (s, 6H).

Example 2.9 Synthesis of7-((3-fluorophenyl)ethynyl)-3-methyl-2-(4-methylmorpholin-3-yl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.4b, Example 1.21d, and Example 1.1.The product was then converted to the corresponding HCl salt. MS (ESI):378 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.29-8.26 (d, J=8.28 Hz, 1H), 7.95(s, 1H), 7.75-7.72 (d, J=8.27 Hz, 1H), 7.49-7.41 (m, 2H), 7.37-7.32 (m,1H), 7.26-7.19 (m, 1H), 5.10-5.16 (d, J=10.5, 3.6 Hz, 1H), 4.56-4.50 (m,1H), 4.27-4.22 (m, 1H), 4.02-3.93 (m, 1H), 3.75-3.71 (m, 2H), 3.68 (s,3H), 3.62-3.57 (m, 1H), 3.01 (s, 3H). mGluR5 PAM EC₅₀: +++++.

Example 2.10 Synthesis of the HCl salt of7-((3-fluorophenyl)ethynyl)-3-methyl-2-(4-methylmorpholin-2-yl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.4b, Example 1.21d, and Example 1.1.The product was then converted to the corresponding HCl salt. MS (ESI):378 (MH⁺).

Example 2.11 Synthesis of7-((3-fluorophenyl)ethynyl)-2-(1-methoxyethyl)-3-methylquinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.1c, and Example 1.1. MS (ESI): 337(MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.27-8.24 (d, J=8.16 Hz, 1H), 7.86 (s,1H), 7.60-7.56 (d, J=8.21 Hz, 1H), 7.38-7.33 (m, 2H), 7.25-7.20 (m, 1H),7.12-7.05 (m, 1H), 4.65 (q, J=6.69 Hz, 1H), 3.74 (s, 3H), 3.40 (s, 3H),1.65-1.60 (d, J=6.69 Hz, 3H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10μM: ++.

Example 2.12 Synthesis of7-((3-fluorophenyl)ethynyl)-2-isobutyl-3-methylquinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.1c, and Example 1.1. MS (ESI): 335(MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.26-8.23 (d, J=8.25 Hz, 1H), 7.83 (s,1H), 7.57-7.53 (d, J=8.25 Hz, 1H), 7.40-7.33 (m, 2H), 7.26-7.25 (m, 1H),7.12-7.05 (m, 1H), 3.62 (s, 3H), 2.75-2.72 (d, J=7.05 Hz, 2H), 2.38-2.29(m, 1H), 1.10-1.05 (d, J=6.63 Hz, 6H). mGluR5 PAM EC₅₀: +++. Fold shiftat 10 μM: +.

Example 2.13 Synthesis of7-((3-fluorophenyl)ethynyl)-2-(2-methoxyethyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.1c, and Example 1.1. MS (ESI): 323(MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 10.00 (brs, 1H), 8.26-8.23 (d, J=8.19Hz, 1H), 7.80 (s, 1H), 7.59-7.56 (dd, J=8.21, 1.5 Hz, 1H), 7.38-7.35 (m,2H), 7.29-7.28 (m, 1H), 7.14-7.07 (m, 1H), 3.84-3.80 (t, J=5.2 Hz, 2H),3.49 (s, 3H), 3.03-2.99 (t, J=5.5 Hz, 2H). mGluR5 PAM EC₅₀: ++. Foldshift at 10 μM: ++.

Example 2.14 Synthesis of2-(sec-butyl)-7-((3-fluorophenyl)ethynyl)-3-methylquinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.1c, and Example 1.1. MS (ESI): 335(MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.26-8.23 (d, J=8.40 Hz, 1H), 7.85 (s,1H), 7.55-7.52 (dd, J=8.1, 1.5 Hz, 1H), 7.38-7.33 (m, 2H), 7.25-7.20 (m,1H), 7.12-7.05 (m, 1H), 3.68 (s, 3H), 3.02-2.95 (m, 1H), 2.05-1.96 (m,1H), 1.72-1.57 (m, 1H), 1.38-1.36 (d, J=6.6 Hz, 3H), 1.02-0.97 (t, J=7.5Hz, 3H). mGluR5 PAM EC₅₀: +.

Example 2.15 Synthesis of the HCl salt of2-(1-methoxyethyl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.1c, and Example 1.1. The productwas then converted to the corresponding HCl salt. MS (ESI): 320 (MH⁺);¹H NMR (300 MHz, CD₃OD) δ 8.95-8.93 (d, J=5.7 Hz, 1H), 8.70-8.64 (m,1H), 8.48-8.45 (d, J=8.3 Hz, 1H), 8.36-8.34 (d, J=7.4 Hz, 2H), 8.17-8.11(m, 1H), 8.06-8.03 (dd, J=8.2, 1.3 Hz, 1H), 5.13-5.07 (m, 1H), 3.85 (s,3H), 3.60 (s, 3H), 1.69-1.67 (d, J=6.6 Hz, 3H).

Example 2.16 Synthesis of the HCl salt of2-(methoxymethyl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.1c, and Example 1.1. The productwas then converted to the corresponding HCl salt. MS (ESI): 306 (MH⁺);¹H NMR (300 MHz, CD₃OD) δ 8.94-8.92 (d, J=5.3 Hz, 1H), 8.68-8.62 (m,1H), 8.48-8.45 (d, J=8.8 Hz, 1H), 8.35-8.32 (d, J=8.6 Hz, 2H), 8.12-8.02(m, 2H), 4.99 (s, 2H), 3.72 (s, 3H), 3.67 (s, 3H).

Example 2.17 Synthesis of the HCl salt of2-(2-methoxypropan-2-yl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.1c, and Example 1.1. The productwas then converted to the corresponding HCl salt. MS (ESI): 334 (MH⁺);¹H NMR (300 MHz, CD₃OD) δ 8.93-8.91 (d, J=5.2 Hz, 1H), 8.71-8.66 (dt,J=8.0, 1.5 Hz, 1H), 8.35-8.32 (d, J=8.2 Hz, 2H), 8.13-8.08 (m, 2H),7.84-7.81 (dd, J=8.2, 1.5 Hz, 1H), 3.95 (s, 3H), 3.26 (s, 3H), 1.75 (s,6H).

Example 2.18 Synthesis of7-((3-fluorophenyl)ethynyl)-2-(methoxymethyl)-3-methylquinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.1. MS (ESI): 323 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ8.29-8.26 (d, J=8.22 Hz, 1H), 7.86 (s, 1H), 7.63-7.60 (d, J=8.21 Hz,1H), 7.38-7.35 (m, 2H), 7.30-7.27 (m, 1H), 7.12-7.09 (m, 1H), 4.60 (s,2H), 3.72 (s, 3H), 3.51 (s, 3H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10μM: ++.

Example 2.19 Synthesis of the HCl salt of2-(1-ethoxyethyl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.1c, and Example 1.1. The productwas then converted to the corresponding HCl salt. MS (ESI): 334 (MH⁺);¹H NMR (300 MHz, CD₃OD) δ 8.91-8.89 (d, J=4.9 Hz, 1H), 8.63-8.57 (dt,J=8.0, 1.5 Hz, 1H), 8.45-8.42 (d, J=8.2 Hz, 1H), 8.30-8.26 (m, 2H),8.08-8.05 (m, 1H), 8.00-7.97 (dd, J=8.2, 1.4 Hz, 1H), 5.16-5.09 (q, 1H),3.77 (s, 3H), 3.75-3.71 (q, 2H), 1.69-1.66 (d, J=6.3 Hz, 3H), 1.37-1.31(t, J=7.0 Hz, 3H).

Example 2.20 Synthesis of the 2HCl salt of3-methyl-2-(1-(methylamino)ethyl)-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.4b, and Example 1.1. The productwas then converted to the corresponding 2HCl salt. MS (ESI): 319 (MH⁺);¹H NMR (300 MHz, CD₃OD) δ 8.94-8.92 (d, J=5.9 Hz, 1H), 8.71-8.66 (dt,J=8.0, 1.5 Hz, 1H), 8.38-8.32 (m, 2H), 8.14-8.09 (m, 2H), 7.88-7.85 (dd,J=8.2, 1.5 Hz, 1H), 4.87-4.83 (m, 1H), 3.69 (s, 3H), 2.86 (s, 3H),1.75-1.72 (d, J=6.9 Hz, 3H).

Example 2.21 Synthesis of2-(1-(dimethylamino)ethyl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.21d. MS (ESI): 333 (MH⁺); ¹H NMR (300 MHz, CD₃OD)δ 8.94-8.92 (d, J=8.0 Hz, 1H), 8.71-8.66 (dt, J=8.0, 1.5 Hz, 1H),8.38-8.32 (m, 2H), 8.17-8.10 (m, 2H), 7.88-7.85 (dd, J=8.2, 1.5 Hz, 1H),5.02-4.95 (m, 1H), 3.70 (s, 3H), 3.16 (s, 3H), 3.03 (s, 3H), 1.78-1.76(d, J=6.9 Hz, 3H). mGluR5 PAM EC₅₀: ++.

Example 2.22 Synthesis of the 2HCl salt of2-(1-(isopropyl(methyl)amino)ethyl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.21d. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 361 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.91-8.89 (d, J=5.0 Hz, 1H), 8.65-8.60 (m, 1H), 8.39-8.36 (d, J=8.3 Hz,1H), 8.30-8.27 (d, J=8.0 Hz, 1H), 8.13 (s, 1H), 8.09-8.04 (dt, J=5.70,1.1 Hz, 1H), 7.89-7.86 (dd, J=8.2, 1.5 Hz, 1H), 5.06-5.04 (m, 1H),3.82-3.76 (m, 1H), 3.69 (s, 3H), 2.89 (s, 3H), 1.76-1.73 (d, J=6.6 Hz,3H), 1.48-1.45 (d, J=6.6 Hz, 3H), 1.34-1.32 (d, J=6.9 Hz, 3H). mGluR5PAM EC₅₀: +.

Example 2.23 Synthesis of the 2HCl salt of2-(1-(cyclobutyl(methyl)amino)ethyl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.21d. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 373 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.95-8.93 (d, J=5.8 Hz, 1H), 8.70-8.67 (dt, J=8.0, 1.4 Hz, 1H),8.38-8.35 (m, 2H), 8.20-8.10 (m, 2H), 7.90-7.87 (dd, J=8.2, 1.4 Hz, 1H),5.03-4.94 (m, 1H), 4.23-4.09 (m, 1H), 3.72 (s, 3H), 3.21-3.18 (m, 1H),3.06-2.97 (m, 3H), 2.39-2.10 (m, 3H), 1.78-1.76 (d, J=6.6 Hz, 3H),0.91-0.78 (m, 1H), 0.46-0.36 (m, 1H). mGluR5 PAM EC₅₀: +.

Example 2.24 Synthesis of the 2HCl salt of2-(azetidin-2-yl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.1c, Example 1.1, and Example 1.21c.The product was then converted to the corresponding 2HCl salt. MS (ESI):317 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.85-8.83 (d, J=5.6 Hz, 1H),8.51-8.46 (t, J=7.7 Hz, 1H), 8.38-7.35 (d, J=8.2 Hz, 1H), 8.19-8.16 (m,2H), 7.97-7.93 (t, J=6.6 Hz, 1H), 7.88-7.84 (d, J=8.2 Hz, 1H), 5.92-5.86(t, J=8.7 Hz, 1H), 4.37-4.28 (m, 1H), 4.15-4.08 (m, 1H), 3.51 (s, 3H),3.19-3.11 (m, 1H), 2.88-2.78 (m, 1H).

Example 2.25 Synthesis of the 2HCl salt of3-methyl-2-(1-methylazetidin-2-yl)-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.21d. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 331 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.94-8.92 (d, J=5.8 Hz, 1H), 8.71-8.65 (t, J=8.0 Hz, 1H), 8.39-8.33 (t,J=8.4 Hz, 2H), 8.22-8.21 (d, J=1.14 Hz, 1H), 8.14-8.09 (t, J=6.85 Hz,1H), 7.90-7.87 (dd, J=8.2, 1.5 Hz, 1H), 5.92-5.85 (t, J=9.1 Hz, 1H),4.31-4.23 (m, 2H), 3.51 (s, 3H), 3.14 (s, 3H), 3.12-3.05 (m, 1H),2.81-2.74 (m, 1H).

Example 2.26 Synthesis of the 2HCl salt of2-(azetidin-3-yl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

Example 2.26a Synthesis of tert-butyl3-(5-bromo-2-(methylcarbamoyl)phenylcarbamoyl)azetidine-1-carboxylate

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b.

Example 2.26b Synthesis of2-(azetidin-3-yl)-7-bromo-3-methylquinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.4b.

Example 2.26c Synthesis of tert-butyl3-(7-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)azetidine-1-carboxylate

The title compound was prepared according to the experimental proceduredescribed in Example 6.20a.

Example 2.26d Synthesis of tert-butyl3-(3-methyl-4-oxo-7-(pyridin-2-ylethynyl)-3,4-dihydroquinazolin-2-yl)azetidine-1-carboxylate

The title compound was prepared according to the experimental proceduredescribed in Example 1.1.

Example 2.26e Synthesis of the 2HCl salt of2-(azetidin-3-yl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.21c. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 317 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.94-8.92 (d, J=5.4 Hz, 1H), 8.71-8.65 (m, 1H), 8.35-8.32 (d, J=8.1 Hz,2H), 8.15-8.09 (m, 2H), 7.86-7.82 (dd, J=8.2, 1.5 Hz, 1H), 4.73-4.48 (m,5H), 3.53 (s, 3H).

Example 2.27 Synthesis of the 2HCl salt of3-methyl-2-(1-methylazetidin-3-yl)-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.21d. The product was converted to thecorresponding 2HCl salt. MS (ESI): 331 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.29-8.26 (d, J=8.22 Hz, 1H), 7.86 (s, 1H), 7.63-7.60 (d, J=8.21 Hz,1H), 7.38-7.35 (m, 2H), 7.30-7.27 (m, 1H), 7.12-7.09 (m, 1H), 4.80 (m,1H), 4.65-4.50 (m, 2H), 4.50-4.40 (m, 2H), 3.51 (s, 3H), 3.04 (s, 3H).

Example 2.28 Synthesis of the 2HCl salt of2-(1-isopropylazetidin-3-yl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.21d. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 359 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.93-8.91 (d, J=5.6 Hz, 1H), 8.70-8.65 (m, 1H), 8.37-8.32 (m, 2H),8.19-8.08 (m, 2H), 7.86-7.82 (m, 1H), 4.83-4.78 (m, 1H), 4.67-4.52 (m,4H), 3.58-3.54 (m, 4H), 1.36-1.33 (m, 6H).

Example 2.29 Synthesis of2-(3-(3-methyl-4-oxo-7-(pyridin-2-ylethynyl)-3,4-dihydroquinazolin-2-yl)azetidin-1-yl)acetonitrile

The mixture of2-(azetidin-3-yl)-3-methyl-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one(100 mg, 0.316 mmol), 2-bromoacetonitrile (0.024 mL, 0.348 mmol), K₂CO₃(87 mg, 0.632 mmol) and CH₃CN (5 mL) was stirred at room temperature for3 h, then diluted with water (10 mL). The mixture was then extractedwith ethyl acetate (3×10 mL). The combined organic layers were driedover Na₂SO₄, filtered, and evaporated to give the crude product, whichwas purified by column chromatography to give 50 mg of the desiredproduct. MS (ESI): 356 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.68-8.67 (d,J=4.4 Hz, 1H), 8.27-8.24 (d, J=8.2 Hz, 1H), 7.95 (s, 1H), 7.77-7.71 (m,1H), 7.67-7.64 (dd, J=8.2, 1.5 Hz, 1H), 7.60-7.58 (d, J=7.8 Hz, 1H),7.33-7.28 (m, 1H), 3.92-3.89 (m, 5H), 3.56 (s, 2H), 3.50 (s, 3H).

Example 2.30 Synthesis of the HCl salt of3-methyl-2-(oxetan-2-yl)-7-(pyridin-2-ylethynyl)quinazolin-4(3H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 2.1b, Example 2.4b, and Example 1.1. The productwas then converted to the corresponding HCl salt. MS (ESI): 318 (MH⁺);¹H NMR (300 MHz, CD₃OD) δ 8.68-8.66 (d, J=4.7 Hz, 1H), 8.30-8.28 (d,J=8.2 Hz, 1H), 8.01-8.00 (d, J=0.9 Hz, 1H), 7.77-7.69 (m, 2H), 7.61-7.58(d, J=7.8 Hz, 1H), 7.33-7.29 (m, 1H), 5.85-5.80 (dd, J=7.8, 6.6 Hz, 1H),4.85-4.79 (m, 1H), 4.72-4.65 (m, 1H), 3.65-3.60 (m, 1H), 3.57 (s, 3H),3.07-3.01 (m, 1H).

Example 3.1 Synthesis of6-((3-fluorophenyl)ethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 305 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.28-8.25 (d, J=8.16 Hz, 1H), 7.80 (s, 1H),7.58-7.55 (d, J=8.24 Hz, 1H), 7.38-7.34 (m, 2H), 7.28-7.26 (m, 1H),7.13-7.06 (m, 1H), 4.25-4.20 (t, J=7.23 Hz, 2H), 3.23-3.18 (t, J=7.95Hz, 2H), 2.37-2.27 (m, 2H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM:+.

Example 3.2 Synthesis of the HCl salt of6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 288 (MH⁺); ¹H NMR(300 MHz, DMSO-d⁶) δ 8.73-8.72 (d, J=4.43 Hz, 1H), 8.23-8.20 (d, J=8.22Hz, 1H), 8.09-8.03 (m, 1H), 7.96 (s, 1H), 7.89-7.86 (d, J=7.80 Hz, 1H),7.77-7.74 (dd, J=8.22, 1.38 Hz, 1H), 7.63-7.58 (m, 1H), 4.14-4.09 (t,J=7.3 Hz, 2H), 3.28-3.22 (t, J=7.89 Hz, 2H), 2.29-2.19 (m, 2H).

Example 3.3 Synthesis of the HCl salt of6-((3-fluorophenyl)ethynyl)-1-((methylamino)methyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

Example 3.3a Synthesis of (5-oxopyrrolidin-2-yl)methyl benzenesulfonate

To a stirred solution of 5-(hydroxymethyl)pyrrolidin-2-one (1.0 g, 8.7mmol) in acetone (80 mL) was added Et₃N (1.8 g, 17.4 mmol) andbenzenesulfonyl chloride (3.1 g, 17.4 mmol). The mixture was stirred for3 h at room temperature. Then the reaction mixture was filtered andconcentrated, and the crude product was purified by columnchromatography to give the desired product. MS (ESI): 256 (MH⁺).

Example 3.3b Synthesis of(6-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-1-yl)methylbenzenesulfonate

The title compound was prepared according to the experimental procedureas described in Example 2.2a. MS (ESI): 435, 437 (MH⁺).

Example 3.3c Synthesis of 6-bromo-1-((methylamino)methyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

To the solution of(6-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-1-yl) methylbenzenesulfonate (100 mg, 0.23 mmol) in acetonitrile (4 mL) was addedaq. methylamine (2 mL). The reaction mixture was stirred at 60° C. for 4h. After concentration, the crude product was purified by columnchromatography to give the desired product. MS (ESI): 308, 310 (MH⁺).

Example 3.3d Synthesis of the HCl salt of64(3-fluorophenyl)ethynyl)-1-((methylamino)methyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 348 (MH⁺). MS (ESI): 348 (MH⁺); ¹H NMR(300 MHz, DMSO-d⁶) δ 8.96-8.83 (m, 2H), 8.18-8.15 (d, J=8.16 Hz, 1H),7.81 (s, 1H), 7.67-7.64 (dd, J=8.19, 1.53 Hz, 1H), 7.56-7.47 (m, 3H),7.37-7.30 (m, 1H), 4.96-4.94 (m, 1H), 3.42-3.31 (m, 3H), 3.06-2.79 (m,1H), 2.66-2.55 (m, 3H), 2.47-2.35 (m, 1H), 2.79-2.22 (m, 1H).

Example 3.4 Synthesis of the HCl salt of1-((dimethylamino)methyl)-6-((3-fluorophenyl)ethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 3.3c and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 362 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.36-8.33 (d, J=8.37 Hz, 1H), 7.85 (s, 1H), 7.79-7.76(dd, J=8.30, 1.31 Hz, 1H), 7.51-7.43 (m, 2H), 7.38-7.34 (m, 1H),7.26-7.19 (m, 1H), 5.25-5.22 (m, 1H), 3.86-3.80 (m, 1H), 3.59-3.45 (m,2H), 3.38-3.33 (m, 1H), 3.19 (s, 3H), 3.05 (s, 3H), 2.77-2.70 (m, 1H),2.30-2.18 (m, 1H). mGluR5 PAM EC₅₀: ++.

Example 3.5 Synthesis of6-((3-fluorophenyl)ethynyl)-1-(hydroxymethyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

Example 3.5a Synthesis of (9H-fluoren-9-yl)methyl(5-oxopyrrolidin-2-yl)methyl carbonate

The title compound was prepared according to the experimental procedureas described in Example 5.1a.

Example 3.5b Synthesis of (9H-fluoren-9-yl)methyl(6-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-1-yl)methylcarbonate

The title compound was prepared according to the experimental procedureas described in Example 2.2a.

Example 3.5c Synthesis of6-bromo-1-(hydroxymethyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 3.17b.

Example 3.5d Synthesis of64(3-fluorophenyl)ethynyl)-1-(hydroxymethyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 358 (MH⁺); ¹H NMR (300 MHz,CD₃OD) δ 8.90-8.88 (d, J=5.0 Hz, 1H), 8.61-8.55 (t, J=7.9 Hz, 1H),8.40-8.37 (d, J=8.3 Hz, 1H), 8.28-8.25 (d, J=7.9 Hz, 1H), 8.06-8.01 (m,2H), 7.91-7.88 (d, J=8.3 Hz, 1H), 4.19 (s, 2H), 3.80-3.75 (t, J=5.1 Hz,4H), 3.36 (s, 2H), 1.90-1.76 (broad, 4H). mGluR5 PAM EC₅₀: +++. Foldshift at 10 μM: +++.

Example 3.6 Synthesis of6-((3-fluorophenyl)ethynyl)-1-(methoxymethyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

Example 3.6a Synthesis of6-bromo-1-(methoxymethyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

A solution of6-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-1-ylbenzenesulfonate (300 mg, 0.69 mmol) and potassium carbonate (290 mg,2.1 mmol) in methanol (80 mL) was stirred at reflux for 2 h. After itwas cooled to room temperature, the mixture was concentrated andpurified by silica-gel chromatography to give the desired product. MS(ESI): 309, 311 (MH⁺).

Example 3.6b Synthesis of64(3-fluorophenyl)ethynyl)-1-(methoxymethyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 349 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.27-8.25 (d, J=8.19 Hz, 1H), 7.80 (s, 1H), 7.58-7.55 (d,J=8.21 Hz, 1H), 7.39-7.33 (m, 2H), 7.31-7.30 (m, 1H), 7.16-7.09 (m, 1H),4.91-4.85 (m, 1H), 4.00-3.95 (m, 1H), 3.69-3.66 (d, J=9.81 Hz, 1H),3.46-3.31 (m, 1H), 3.33 (s, 3H), 3.07-2.97 (m, 1H), 2.45-2.28 (m, 2H).mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 3.7 Synthesis of the HCl salt of1-(methoxymethyl)-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 332 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ8.68-8.66 (d, J=4.86 Hz, 1H), 8.19-8.16 (d, J=8.19 Hz, 1H), 7.97-7.92(m, 1H), 7.82-7.76 (m, 2H), 7.69-7.66 (d, J=7.62 Hz, 1H), 7.53-7.48 (m,1H), 4.81-4.77 (m, 1H), 3.84-3.79 (m, 1H), 3.64-3.60 (d, J=9.75 Hz, 1H),3.26-3.17 (m, 4H), 3.02-2.98 (m, 1H), 2.39-2.31 (m, 1H), 2.17-2.10 (m,1H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++.

Example 3.8 Synthesis of64(3-fluorophenyl)ethynyl)-2-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 319 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.28-8.25 (d, J=8.19 Hz, 1H), 7.77 (s, 1H),7.58-7.55 (d, J=8.24 Hz, 1H), 7.41-7.34 (m, 2H), 7.32-7.28 (m, 1H),7.13-7.06 (m, 1H), 4.40-4.34 (m, 1H), 3.78-3.72 (m, 1H), 3.35-3.27 (m,1H), 2.87-2.71 (m, 2H), 1.30-1.28 (d, J=6.63 Hz, 3H). mGluR5 PAM EC₅₀:+++++. Fold shift at 10 μM: ++.

Example 3.9 Synthesis of6-((3-fluorophenyl)ethynyl)-2-isobutyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 361 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.28-8.25 (d, J=8.25 Hz, 1H), 7.79 (s, 1H),7.58-7.55 (d, J=8.22 Hz, 1H), 7.37-7.34 (m, 2H), 7.32-7.28 (m, 1H),7.13-7.07 (m, 1H), 4.44-4.37 (m, 1H), 3.76-3.69 (m, 1H), 3.32-3.24 (m,1H), 2.90-2.81 (m, 1H), 2.76-2.65 (m, 1H), 1.76-1.67 (m, 1H), 1.52-1.47(t, J=7.28 Hz, 2H), 1.00-0.97 (d, J=6.54 Hz, 6H). mGluR5 PAM EC₅₀: ++++.

Example 3.10 Synthesis of2-benzyl-64(3-fluorophenyl)ethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 395 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.27-8.24 (d, J=8.16 Hz, 1H), 7.79 (s, 1H),7.59-7.55 (d, J=8.21 Hz, 1H), 7.38-7.33 (m, 4H), 7.30-7.29 (m, 1H),7.26-7.22 (m, 3H), 7.14-7.07 (m, 1H), 4.31-4.24 (m, 1H), 3.95-3.89 (m,1H), 3.32-3.22 (m, 1H), 3.03-2.84 (m, 4H). mGluR5 PAM EC₅₀: +++++. Foldshift at 10 μM: ++.

Example 3.11 Synthesis of the HCl salt of2-methyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 302 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ8.72-8.71 (d, J=4.38 Hz, 1H), 8.21-8.18 (d, J=8.22 Hz, 1H), 8.08-8.02(m, 1H), 7.93-7.92 (d, J=1.08 Hz, 1H), 7.88-7.85 (d, J=7.80 Hz, 1H),7.76-7.72 (d, J=8.22 Hz, 1H), 7.62-7.58 (dd, J=7.60, 1.04 Hz, 1H), 5.45(s, 1H), 4.30-4.23 (dd, J=11.76, 6.69 Hz, 1H), 3.69-3.63 (dd, J=11.76,6.69 Hz, 1H), 3.40-3.31 (m, 1H), 2.93-2.85 (m, 1H), 2.76-2.69 (m, 1H),1.18-1.16 (d, J=6.6 Hz, 3H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM:+++.

Example 3.12 and Example 3.13 Separation of(S)-2-methyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-oneand(R)-2-methyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

Racemic2-methyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-onewas separated into the corresponding two single enantiomer compoundsS)-2-methyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-oneand(R)-2-methyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 3.0×25.0 cm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was methanol:isopropanol (1:1) with 1%isopropylamine. Isocratic Method: 50% Co-solvent at 70 mL/min SystemPressure: 200 bar. Column Temperature 25° C.

Faster moving enantiomer (fraction 1) Retention time=2.1 min 100% ee.mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.Slower moving enantiomer (fraction 2): Retention time=3.3 min. 95.6% ee.mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: +++.

Example 3.14 Synthesis of1-methyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 302 (MH⁺); ¹HNMR (300 MHz, CD₃OD) δ 8.99-8.97 (dd, J=5.08, 0.83 Hz, 1H), 8.76-8.70(t, J=7.99 Hz, 1H), 8.47-8.45 (d, J=8.28 Hz, 1H), 8.42-8.39 (d, J=7.98Hz, 1H), 8.19-8.14 (m, 2H), 8.07-8.04 (dd, J=8.28, 1.38 Hz, 1H),5.08-5.02 (m, 1H), 3.81-3.72 (m, 1H), 3.58-3.47 (m, 1H), 2.74-2.66 (m,1H), 2.22-2.15 (m, 1H), 1.63-1.61 (d, J=6.54 Hz, 3H). mGluR5 PAM EC₅₀:++.

Example 3.15 Synthesis of the HCl salt of6′-((3-fluorophenyl)ethynyl)-1′H-spiro[piperidine-2,2′-pyrrolo[2,1-b]quinazolin]-9′(3′H)-one

Example 3.15a Synthesis of tert-butyl6′-bromo-9′-oxo-3′,9′-dihydro-1′H-spiro[piperidine-2,2′-pyrrolo[2,1-b]quinazoline]-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 2.2a. MS (ESI): 434, 436 (MH⁺).

Example 3.15b Synthesis of6′-bromo-1′H-spiro[piperidine-2,2′-pyrrolo[2,1-b]quinazolin]-9′(3′H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.21c. MS (ESI): 334, 336 (MH⁺)

Example 3.15c Synthesis of the HCl salt of6′((3-fluorophenyl)ethynyl)-1′H-spiro[piperidine-2,2′-pyrrolo[2,1-b]quinazolin]-9′(3′H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The title compound was then converted tothe corresponding HCl salt. MS (ESI): 374 (M 1-1^(±)); ¹H NMR (300 MHz,CD₃OD) δ 8.29-8.26 (d, J=8.61 Hz, 1H), 7.84 (s, 1H), 7.74-7.71 (dd,J=8.25, 1.52 Hz, 1H), 7.78-7.42 (m, 2H), 7.39-7.34 (m, 1H), 7.25-7.21(m, 1H), 4.66-4.61 (d, J=13.86 Hz, 1H), 4.36-4.31 (d, J=13.92 Hz, 1H),3.67 (s, 2H), 3.42-3.41 (m, 2H), 2.14-2.03 (m, 2H), 1.88 (broad, 4H).

Example 3.16 Synthesis of6′-((3-fluorophenyl)ethynyl)-1-methyl-1′H-spiro[piperidine-2,2′-pyrrolo[2,1-b]quinazolin]-9′(3′H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.21d. MS (ESI): 388 (MH⁺); ¹H NMR (300 MHz,DMSO-d⁶) δ 8.28-8.25 (d, J=8.27 Hz, 1H), 7.79 (s, 1H), 7.59-7.55 (dd,J=8.24, 1.52 Hz, 1H) 7.38-7.34 (m, 2H), 7.30-7.29 (m, 1H), 7.28-7.26 (m,1H), 7.14-7.07 (m, 1H), 4.48-4.44 (d, J=13.42 Hz, 1H), 4.11-4.09 (d,J=6.75 Hz, 1H), 3.86-3.81 (d, J=13.42 Hz, 1H), 3.44-3.38 (d, J=18.33 Hz,1H), 3.06-3.00 (d, J=18.36 Hz, 1H), 2.60-2.57 (m, 2H), 2.14 (s, 3H),1.86-1.82 (m, 2H), 1.71-1.59 (m, 2H), 1.02-0.99 (d, J=6.72 Hz, 1H).mGluR5 PAM EC₅₀:

++.

Example 3.17 Synthesis of the HCl salt of6′-((3-fluorophenyl)ethynyl)-1′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]quinazolin]-9′(3H)-one

Example 3.17a Synthesis of (9H-fluoren-9-yl)methyl6′-bromo-9′-oxo-3′,9′-dihydro-1′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]quinazoline]-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 2.2a.

Example 3.17b Synthesis of6′-bromo-1′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]quinazolin]-9′(3′H)-one

A solution of (9H-fluoren-9-yl)methyl6′-bromo-9′-oxo-3′,9′-dihydro-1′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]quinazoline]-1-carboxylate(0.6 g, 1.1 mmol, 1 equiv) and piperidine (4 mL) in DCM (50 mL) wasstirred at room temperature overnight. The reaction mixture was thendiluted with water and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were dried over Na₂SO₄. After filtration andconcentration, the residue was purified by silica gel chromatography togive the desired product.

Example 3.17c Synthesis of the HCl salt of6′4(3-fluorophenyl)ethynyl)-1′H-spiro[piperidine-4,2′-pyrrolo[2,1-b]quinazolin]-9′(3′H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The compound was then converted to thecorresponding HCl salt. MS (ESI): 374 (M+H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.34-8.31 (d, J=8.25 Hz, 1H), 7.85-7.80 (m, 2H), 7.50-7.43 (m, 2H),7.40-7.36 (m, 1H), 7.27-7.20 (m, 1H), 4.28 (s, 2H), 3.54 (s, 2H),3.38-3.36 (m, 5H), 2.12-2.08 (m, 3H).

Example 3.18 Synthesis of2-(hydroxymethyl)-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.1a, Example 2.2a, 3.17b, and Example 1.1. MS(ESI): 318 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ 8.87-8.68 (d, J=4.44 Hz,1H), 8.19-8.16 (d, J=8.25 Hz, 1H), 8.01-7.96 (m, 1H), 7.87-7.80 (m, 2H),7.71-7.68 (d, J=8.34 Hz, 1H), 7.56-7.52 (m, 1H), 4.19-4.12 (m, 1H),3.94-3.88 (m, 1H), 3.54-3.44 (m, 2H), 3.52-3.24 (m, 1H), 3.03-2.95 (m,1H), 2.72 (m, 1H). mGluR5 PAM EC₅₀: ++.

Example 3.19 Synthesis of the HCl salt of2-(methoxymethyl)-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.25. The product was then converted to thecorresponding HCl salt. MS (ESI): 332 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.92-8.90 (d, J=5.55 Hz, 1H), 8.64-8.58 (m, 1H), 8.43-8.40 (d, J=8.22Hz, 1H), 8.31-8.28 (d, J=8.01 Hz, 1H), 8.09-8.04 (m, 2H), 7.97-7.95 (d,J=8.28 Hz, 1H), 4.47-4.41 (m, 1H), 4.20-4.14 (m, 1H), 3.68-3.58 (m, 3H),3.40 (s, 3H), 3.33-3.32 (m, 1H), 3.12-3.08 (m, 1H). mGluR5 PAM EC₅₀:+++.

Example 3.20 Synthesis of2,2-dimethyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 316 (MH⁺); ¹HNMR (300 MHz, DMSO-d⁶) δ 8.68-8.67 (d, J=4.62 Hz, 1H), 8.19-8.16 (d,J=8.22 Hz, 1H), 7.99-7.97 (m, 1H), 7.84-7.78 (m, 2H), 7.70-7.67 (d,J=8.19 Hz, 1H), 7.54-7.50 (m, 1H), 3.84 (s, 2H), 2.98 (s, 2H), 1.20 (s,6H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: +++.

Example 3.21 Synthesis of the HCl salt of3-methyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

Example 3.21a Synthesis of N-trimethylsilyl-2-pyrrolidinone

A solution of 30.0 g (353 mmol) of 2-pyrrolidinone and 35.5 g (353 mmol)of triethylamine in 250 mL of benzene was refluxed, during which 210 mL(179.8 g, 1655 mmol) of chlorotrimethysilane was added dropwise over 1h. After 12 h, the solution was cooled, filtered and the precipitate waswashed with benzene. Concentration of the filtrate under vacuum pressuregave a yellow oil, which was distilled (0.3 mmHg) to give 37.1 g ofN-timethylsilyl-2-pyrrolidinone as a colorless oil. MS (ESI): 158 (MH⁺).

Example 3.21b Synthesis of 3-methyl-2-pyrrolidinone and3,3-dimethylpyrrolidin-2-one

A solution of lithium diisopropylamide in 100 mL of THF (prepared from4.88 mL (3.54 g, 35.0 mmol) of diisopropylamine and 22.1 mL of 2.5 Mn-butyllithium in hexane) was treated with 3.80 g (35.0 mmol) ofN-trimethylsilyl-2-pyrrolidinone at −78° C. After one hour, 4.48 g (35.0mmol) of iodomethane was added at −78° C. The solution was warmed to 0°C. and stirred for 12 hours. The reaction mixture was then quenched withwater and extracted with ethyl acetate. The organic layer was then driedover MgSO₄. After removal of solvent, 2.8 g of the crude product wasobtained which was directly used for the next step without furtherpurification.

Example 3.21c Synthesis of6-bromo-3-methyl-2,3-dihydropyrrolo[2,1-b]-quinazolin-9(1H)-one and6-bromo-3,3-dimethyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compounds were prepared according to the experimentalprocedure described in Example 4.27b. The title compounds were separatedin this step.

Example 3.21d Synthesis of the HCl salt of3-methyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 302 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.94-8.92 (d, J=5.6 Hz, 1H), 8.66-8.61 (t, J=8.0 Hz, 1H), 8.43-8.41 (d,J=8.3 Hz, 1H), 8.33-8.31 (d, J=8.0 Hz, 1H), 8.16 (s, 1H), 8.11-8.06 (t,J=6.0 Hz, 1H), 7.98-7.95 (dd, J=8.3, 1.3 Hz, 1H), 4.46-4.37 (m, 1H),4.26-4.16 (m, 1H), 3.84-3.78 (m, 1H), 2.72-2.63 (m, 1H), 2.12-2.05 (m,1H), 1.63-1.60 (d, J=7.1 Hz, 3H).

Example 3.22 Synthesis of the HCl salt3,3-dimethyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 316 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.67-8.66 (d, J=4.7 Hz, 1H), 8.19-8.16 (d, J=8.3 Hz, 1H), 7.97-7.92 (m,1H), 7.88 (s, 1H), 7.78-7.75 (d, J=7.8 Hz, 1H), 7.68-7.65 (dd, J=8.2,1.3 Hz, 1H), 7.52-7.48 (m, 1H), 4.08-4.03 (t, J=7.1 Hz, 2H), 2.11-2.06(t, J=7.1 Hz, 2H), 1.36 (s, 6H).

Example 3.23 Synthesis of the HCl salt of2,2-dimethyl-6-(pyridin-2-ylethynyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 316 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.91-8.89 (d, J=5.85 Hz, 1H), 8.62-8.56 (t, J=7.93Hz, 1H), 8.42-8.39 (d, J=8.28 Hz, 1H), 8.29-8.26 (d, J=8.10 Hz, 1H),8.07-8.02 (m, 2H), 7.94-7.91 (dd, J=7.93, 1.40 Hz, 1H), 4.07 (s, 2H),3.28 (s, 2H), 1.36 (s, 6H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM:+++.

Example 3.24 Synthesis of the HCl salt of6′-(pyridin-2-ylethynyl)-2,3,5,6-tetrahydro-1′H-spiro[pyran-4,2′-pyrrolo[2,1-b]quinazolin]-9′(3′H)-one

The title compound was prepared according to the experimental proceduresas described in Example 4.27b and Example 1.1. The product was thenconverted to the corresponding HCl salt. mGluR5 PAM EC₅₀: ++++. Foldshift at 10 μM: +++.

Example 3.25 Synthesis of3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-6,9-methanopyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 314 (MH⁺); ¹HNMR (300 MHz, CD₃OD) δ 8.95-8.93 (d, J=5.64 Hz, 1H), 8.71-8.68 (t,J=7.97 Hz, 1H), 8.43-8.40 (d, J=8.25 Hz, 1H), 8.36-8.33 (d, J=8.04 Hz,1H), 8.14-8.09 (m, 2H), 7.98-7.95 (dd, J=8.28, 1.35 Hz, 1H), 5.37 (s,1H), 3.87-3.86 (m, 1H), 2.45-2.31 (m, 2H), 2.27-2.20 (m, 1H), 2.04-2.00(d, J=10.41 Hz, 1H), 1.88-1.75 (m, 2H). mGluR5 PAM EC₅₀: ++++. ++++.Fold shift at 10 μM: +.

Example 4.1 Synthesis of9-((3-fluorophenyl)ethynyl)-3,4-dihydro-[1,4]oxazino[3,4-b]quinzolin-6(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 321 (M+H⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.17-8.14 (d, J=8.67 Hz, 1H), 7.75 (s, 1H),7.64-7.61 (d, J=8.52 Hz, 1H), 7.51 (s, 3H), 7.36-7.32 (m, 1H), 4.71 (s,2H), 4.09 (t, 2H), 3.91 (t, 2H). mGluR5 PAM EC₅₀: +++++.

Example 4.2 Synthesis of9-((4-fluorophenyl)ethynyl)-3,4-dihydro-[1,4]oxazino[3,4-b]quinazolin-6(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 321 (MH⁺) δ ¹H NMR (300 MHz,CDCl₃) δ 8.27-8.24 (d, J=8.88 Hz, 1H), 7.75 (s, 1H), 7.58-7.56 (d,J=6.51 Hz, 3H), 7.12-7.07 (t, J=8.15 Hz, 2H), 4.78 (s, 2H), 4.16-4.10(m, 4H). mGluR5 PAM EC₅₀: +++.

Example 4.3 Synthesis of the HCl salt of9-(pyridin-2-ylethynyl)-3,4-dihydro-[1,4]oxazino[3,4-b]quinazolin-6(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 304 (M+H⁺); ¹H NMR (300 MHz, DMSO-d⁶)δ 8.723-8.707 (d, J=4.50 Hz, 1H), 8.202-8.175 (d, J=8.224 Hz, 1H),8.084-8.036 (m, 2H), 7.874-7.855 (m, 2H), 7.716-7.688 (m, 1H),7.624-7.583 (m, 1H), 4.745 (s, 2H), 4.115-4.081 (t, J=5.1 Hz, 2H),3.935-3.901 (t, J=5.1 Hz, 2H).

Example 4.4 Synthesis of3-((3-fluorophenyl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b)]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 319 (M+H⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.26-8.23 (d, J=8.25, Hz, 1H), 7.76 (s, 1H),7.75-7.53 (dd, J=8.24, 1.43 Hz, 1H), 7.38-7.32 (m, 2H), 7.30-7.26 (m,1H), 7.13-7.07 (m, 1H), 4.12-4.08 (t, J=6.0 Hz, 2H), 3.05-3.00 (t,J=6.12 Hz, 2H), 2.08-1.94 (m, 4H). mGluR5 PAM EC₅₀: +++++. Fold shift at10 μM: ++.

Example 4.5 Synthesis of3-((4-fluorophenyl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 319 (M+H⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.23-8.20 (d, J=8.22 Hz, 1H), 7.72 (s, 1H), 7.57-7.44 (m, 3H),7.10-7.04 (t, J=8.48 Hz, 2H), 4.09-4.05 (t, J=5.84, Hz, 2H), 3.02-2.98(t, J=6.30, Hz, 2H), 2.25-1.95 (m, 4H). mGluR5 PAM EC₅₀: +++++.

Example 4.6 Synthesis of the HCl salt of3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 302 (M+H⁺); ¹H NMR (300 MHz, DMSO-d⁶)δ 8.71-8.69 (d, J=4.62 Hz, 1H), 8.26-8.22 (d, J=8.78 Hz, 1H), 8.10 (s,1H), 8.02-7.97 (t, J=7.70 Hz, 1H), 7.85-7.81 (m, 2H), 7.58-7.54 (m, 1H),3.98-3.94 (t, J=5.97 Hz, 2H), 3.22-3.18 (t, J=6.35 Hz, 2H), 2.01-1.86(m, 4H).

Example 4.7 Synthesis of6-allyl-3-((3-fluorophenyl)ethynyl)-8,9-dihydro-6H-Pyrido[2,1-b]quinazolin-11(7H)-one

Example 4.7a Synthesis of 3-allylpiperidin-2-one

To a solution of piperidin-2-one (0.5 g, 5.0 mmol, 1 equiv) in dry THF(10.0 mL) was added nBuLi (4.2 ml, 10.5 mmol, 2.1 equiv) dropwise at 0°C. The mixture was then cooled to −75° C. and excess 3-bromoprop-1-enewas added to the mixture. The reaction mixture was kept at −78° C. for 1h, quenched with NH₄Cl solution and extracted with ethyl acetate (3×20mL). The combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure to give the desired product, which was directlyused for the next step without further purification.

Example 4.7b Synthesis of6-allyl-3-bromo-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a.

Example 4.7c Synthesis of6-allyl-3-((3-fluorophenyl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 359 (M+H⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.26-8.23 (d, J=7.83 Hz, 1H), 7.82 (s, 1H), 7.56-7.53 (dd,J=8.74, 1.52 Hz, 1H), 7.38-7.35 (m, 2H), 7.28-7.26 (m, 1H), 7.12-7.09(m, 1H), 5.96-5.82 (m, 1H), 5.19-5.11 (m, 2H), 4.19-4.16 (m, 1H),4.02-4.00 (m, 1H), 3.01-2.94 (m, 2H), 2.54-2.53 (m, 1H), 2.10-1.96 (m,3H), 1.72-1.69 (m, 1H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: +.

Example 4.8 Synthesis of6-ethyl-3-((3-fluorophenyl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.7a, Example 2.2a and Example 1.1. MS (ESI):347 (M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.26-8.23 (d, J=8.01 Hz, 1H), 7.82(s, 1H), 7.55-7.52 (dd, J=8.27, 1.49 Hz, 1H), 7.38-7.34 (m, 2H),7.28-7.27 (m, 1H), 7.11-7.09 (m, 1H), 4.22-4.13 (m, 1H), 4.07-3.99 (m,1H), 2.86-2.81 (m, 1H), 2.27-1.94 (m, 4H), 1.81-1.68 (m, 2H), 1.10-1.02(m, 3H). mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM: +.

Example 4.9 Synthesis of6-benzyl-3-((3-fluorophenyl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.7a, Example 2.2a and Example 1.1. MS (ESI):409 (M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.28-8.25 (d, J=8.34 Hz, 1H), 7.88(s, 1H), 7.74-7.69 (m, 1H), 7.58-7.55 (dd, J=8.24, 1.52 Hz, 1H),7.40-7.34 (m, 4H), 7.33-7.29 (m, 3H), 7.14-7.07 (m, 1H), 4.17-4.16 (m,1H), 3.98-3.95 (m, 1H), 3.74-3.68 (m, 1H), 3.23-3.17 (m, 1H), 2.94-2.86(m, 2H), 1.99-1.90 (m, 3H). mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM:++.

Example 4.10 Synthesis of3-((3-fluorophenyl)ethynyl)-7-methyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 333 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.26-8.23 (d, J=8.27 Hz, 1H), 7.77 (s, 1H),7.56-7.52 (dd, J=8.74, 1.52 Hz, 1H), 7.38-7.34 (m, 2H), 7.30-7.25 (m,1H), 7.14-7.06 (m, 1H), 4.41-4.33 (m, 1H), 3.88-3.78 (m, 1H), 3.16-3.08(m, 1H), 2.67-2.58 (m, 1H), 2.23-2.09 (m, 2H), 1.62-1.55 (m, 1H),1.18-1.16 (d, J=6.6 Hz, 3H). mGluR5 PAM EC₅₀: +++++.

Example 4.11 and Example 4.12 Synthesis of7-methyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-oneand8-methyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

Example 4.11a Synthesis of 3-methylcyclopentanone oxime

A solution of 3-methylcyclopentanone (2 g, 20.4 mmol), hydroxylaminehydrochloride (2.6 g, 40.8 mmol) and Na₂CO₃ (6.48 g, 61.2 mmol) inMeOH/water (20 mL/12 mL) was stirred at room temperature for 5 h. Thesolvent was then removed from the reaction mixture under reducedpressure. The residue was partitioned between ethyl acetate and water,and the organic layer was washed with brine, dried over anhydrous sodiumsulfate, and stripped of all solvents under reduced pressure to providethe crude for the next step.

Example 4.11b Synthesis of 4-methylpiperidin-2-one and5-methylpiperidin-2-one

To a solution of 3-methylcyclopentanone oxime (2 g, 17.7 mmol) andNa₂CO₃ (7.5 g, 70.8 mmol) in acetone (100 mL) and water (100 mL) wasadded phenylsulfonyl chloride (6.18 g, 35.4 mmol) dropwise at 0° C. Thereaction mixture was stirred overnight, quenched with water, andextracted with DCM (3×200 mL). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure to give the desiredproduct.

Example 4.11c and Example 4.12c Synthesis of3-bromo-7-methyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one and3-bromo-8-methyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compounds were prepared according to the experimentalprocedure as described in Example 2.2a.

Example 4.11d and Example 4.12d Synthesis of the HCl salt of7-methyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-oneand HCl salt of8-methyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The products were then converted to thecorresponding HCl salt.

7-methyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

MS (ESI): 316 (M+H⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ 8.72-8.70 (d, J=4.56Hz, 1H), 8.26-8.24 (d, J=8.28 Hz, 1H), 8.16 (s, 1H), 8.05-7.99 (m, 1H),7.88-7.83 (m, 2H), 7.60-7.56 (m, 1H), 4.25-4.17 (m, 1H), 3.80-3.70 (m,1H), 3.37-3.30 (dd, J=17.84, 3.73 Hz, 1H), 2.87-2.78 (m, 1H), 2.12-2.09(m, 2H), 1.66-1.57 (m, 1H), 1.10-1.08 (d, J=6.6 Hz, 3H). mGluR5 PAMEC₅₀: +++. Fold shift at 10 μM: +.

8-methyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

MS (ESI): 316 (M+H⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ 8.71-8.70 (d, J=4.47Hz, 1H), 8.26-8.24 (d, J=8.28 Hz, 1H), 8.11 (s, 1H), 8.023-7.98 (m, 1H),7.86-7.81 (t, J=7.56 Hz, 2H), 7.58-7.54 (m, 1H), 4.31-4.25 (dd, J=13.67,4.76 Hz, 1H), 3.31-3.19 (m, 3H), 2.11-2.096 (m, 2H), 1.56-1.50 (m, 1H),1.10-1.08 (d, J=6.51 Hz, 3H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10μM: +.

Example 4.13 and Example 4.14 Synthesis of3-((3-fluorophenyl)ethynyl)-7,7-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-oneand3-((3-fluorophenyl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.11a, Example 4.11b, Example 2.2a, and Example1.1.

3-((3-fluorophenyl)ethynyl)-7,7-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

MS (ESI): 347 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.27-8.24 (d, J=8.2 Hz,1H), 7.76 (s, 1H), 7.56-7.53 (d, J=8.21, 1H), 7.37-7.35 (m, 2H),7.30-7.25 (m, 1H), 7.14-7.05 (m, 1H), 4.12-4.08 (t, J=6.6 Hz, 2H), 2.80(s, 2H), 1.87-1.83 (t, J=6.6 Hz, 2H), 1.14 (s, 6H). mGluR5 PAM EC₅₀:+++++. Fold shift at 10 μM: ++.

3-((3-fluorophenyl)ethynyl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

MS (ESI): 347 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.27-8.24 (d, J=8.2 Hz,1H), 7.76 (s, 1H), 7.56-7.53 (dd, J=8.21, 1.5 Hz, 1H), 7.37-7.35 (m,2H), 7.27-7.25 (m, 1H), 7.14-7.05 (m, 1H), 3.84 (s, 2H), 3.06-3.01 (t,J=7.1 Hz, 2H), 1.79-1.74 (t, J=7.1 Hz, 2H), 1.12 (s, 6H). mGluR5 PAMEC₅₀: +++++. Fold shift at 10 μM: ++.

Example 4.15 and Example 4.16 Synthesis of the HCl salt of7,7-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-oneand HCl salt of8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-1)]quinazolin-11(7H)-one

The title compounds were prepared according to the experimentalprocedures as described in Example 1.1. The products were then convertedto the corresponding HCl salts.

8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

MS (ESI): 330 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.95-8.93 (d, J=5.7 Hz,1H), 8.68-8.63 (dt, J=8.0, 1.5 Hz, 1H), 8.46-8.44 (d, J=8.3 Hz, 1H),8.35-8.33 (d, J=8.0 Hz, 1H), 8.13-8.08 (m, 2H), 8.03-8.00 (dd, J=8.3,1.4 Hz, 1H), 3.89 (s, 2H), 3.41-3.36 (t, J=6.8 Hz, 2H), 1.91-1.87 (t,J=6.8 Hz, 2H), 1.20 (s, 6H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10μM: +++.

7,7-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

MS (ESI): 330 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.89-8.87 (d, J=5.9 Hz,1H), 8.53-8.52 (m, 1H), 8.46-8.44 (d, J=8.3 Hz, 1H), 8.24-8.21 (d, J=8.0Hz, 1H), 8.03-7.97 (m, 3H), 4.22-4.12 (t, J=6.5, 1.4 Hz, 2H), 3.11 (s,2H), 2.02-1.99 (t, J=6.4 Hz, 2H), 1.23 (s, 6H). mGluR5 PAM EC₅₀: +++++.Fold shift at 10 μM: +++.

Example 4.17 Synthesis of3-((3-fluorophenyl)ethynyl)-9-methyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 333 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.27-8.24 (d, J=8.2 Hz, 1H), 7.74 (s, 1H),7.55-7.51 (d, J=8.21, 1H), 7.37-7.35 (m, 2H), 7.30-7.28 (m, 1H),7.11-7.07 (m, 1H), 5.12-5.10 (m, 1H), 3.09-3.01 (m, 2H), 2.02-1.98 (m,4H), 1.43-1.41 (d, J=6.6 Hz, 3H). mGluR5 PAM EC₅₀: ++++.

Example 4.18 Synthesis of the HCl salt of9-methyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 316 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.70-8.68 (d, J=4.3 Hz, 1H), 8.25-8.22 (d, J=8.2 Hz,1H), 8.02 (s, 1H), 8.00-7.94 (m, 1H), 7.83-7.77 (m, 2H), 7.56-7.51 (m,1H), 4.98-4.90 (m, 1H), 3.39-3.10 (m, 2H), 2.00-1.87 (m, 4H), 1.34-1.32(d, J=6.6 Hz, 3H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: ++.

Example 4.19 Synthesis of the HCl salt of9-ethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 333 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.70-8.68 (d, J=4.5 Hz, 1H), 8.25-8.22 (d, J=8.2 Hz,1H), 8.06 (s, 1H), 8.00-7.95 (m, 1H), 7.84-7.79 (m, 2H), 7.56-7.52 (m,1H), 4.70-4.65 (m, 1H), 3.25-3.14 (m, 2H), 2.10-2.06 (m, 1H), 1.88-1.84(m, 3H), 1.74-1.61 (m, 2H), 0.96-0.91 (t, J=7.3 Hz, 3H). mGluR5 PAMEC₅₀: ++++. Fold shift at 10 μM: ++.

Example 4.20 Synthesis of3-((3-fluorophenyl)ethynyl)-8H-pyrido[2,1-b]quinazolin-11(9H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 317 (M+H⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.28-8.25 (d, J=8.22 Hz, 1H), 7.82 (s, 1H),7.58-7.55 (dd, J=8.72, 1.47 Hz, 1H), 7.38-7.35 (m, 2H), 7.29-7.28 (m,1H), 7.13-7.07 (m, 1H), 6.78-6.71 (m, 1H), 6.54-6.50 (m, 1H), 4.32-4.27(t, J=7.01 Hz, 2H), 2.66-2.59 (m, 2H). mGluR5 PAM EC₅₀: ++++.

Example 4.21 Synthesis of3′4(3-fluorophenyl)ethynyl)-6′,7′-dihydrospiro[[1,3]dioxolane-2,8′-pyrido[2,1-b]quinazolin]-11′(9′H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 377 (M+H⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.26-8.23 (d, J=8.19 Hz, 1H), 7.78 (s, 1H),7.57-7.54 (dd, J=8.24, 1.52 Hz, 1H), 7.41-7.30 (m, 2H), 7.29-7.26 (m,1H), 7.14-7.08 (m, 1H), 4.09 (broad s, 6H), 3.21-3.16 (t, J=7.10 Hz,2H), 2.22-2.18 (t, J=7.11 Hz, 2H). mGluR5 PAM EC₅₀: ++++. Fold shift at10 μM: ++.

Example 4.22 Synthesis of3-((3-fluorophenyl)ethynyl)-6H-pyrido[2,1-b]quinazoline-8,11(7H,9H)-dione

A solution of3′((3-fluorophenyl)ethynyl)-6′,7′-dihydrospiro[[1,3]dioxolane-2,8′-pyrido[2,1-b]quinazolin]-11′(9′H)-one(0.5 g, 1.3 mmol) and 4N HCl (4 mL) in THF (20 mL) was heated at refluxfor 4 h. After it was cooled to room temperature, the reaction mixturewas quenched with Na₂CO₃ solution and extracted with ethyl acetate (3×50mL). The combined organic layers were dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by silica gelchromatography to give the desired product. MS (ESI): 333 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.28-8.25 (d, J=8.19 Hz, 1H), 7.82 (s, 1H), 7.63-7.60(dd, J=8.22, 1.50 Hz, 1H), 7.39-7.35 (m, 2H), 7.28-7.27 (m, 1H),7.15-7.09 (m, 1H), 4.28 (s, 2H), 3.34-3.30 (t, 2H), 2.85-2.81 (t, 2H).mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +.

Example 4.23 Synthesis of3-((3-fluorophenyl)ethynyl)-8-hydroxy-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

To a solution of3-((3-fluorophenyl)ethynyl)-6H-pyrido[2,1-b]quinazoline-8,11(7H,9H)-dione (0.2 g, 0.6 mmol, 1 equiv) in THF (15 mL) was added NaBH₄(45.6 mg, 1.2 mmol, 2 equiv) in portions. After stirring at rt for 30minute, the reaction mixture was quenched with water and extracted withethyl acetate (3×50 mL). The combined organic layers were dried overNa₂SO₄. After filtration and concentration, the residue was purified bysilica gel chromatography to give the desired product. MS (ESI): 335(M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.21 (d, J=8.19 Hz, 1H), 7.76 (s,1H), 7.56-7.53 (dd, J=8.22, 1.41 Hz, 1H), 7.37-7.34 (m, 2H), 7.27-7.26(m, 1H), 7.13-7.06 (m, 1H), 4.53-4.51 (m, 1H), 4.34-4.28 (m, 1H),4.05-3.99 (m, 1H), 3.52-3.22 (m, 1H), 3.03-2.93 (m, 1H), 2.23-2.16 (m,1H), 2.11-2.02 (m, 2H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.

Example 4.24 Synthesis of the HCl salt of8-hydroxy-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1, Example 4.22, and Example 4.23. The productwas then converted to the corresponding HCl salt. MS (ESI): 318 (M+H⁺);¹H NMR (300 MHz, CD₃OD) δ 8.86-8.84 (d, J=4.952 Hz, 1H), 8.49-8.41 (m,2H), 8.19-8.16 (d, J=7.954 Hz, 1H), 8.00-7.92 (m, 3H), 4.51-4.47 (m,1H), 4.34-4.29 (dd, J=5.08, 3.37 Hz, 1H), 4.01-3.95 (dd, J=7.25, 1.63Hz, 1H), 3.54-3.43 (m, 1H), 3.28-3.21 (m, 1H), 2.21-2.12 (m, 2H). mGluR5PAM EC₅₀: +.

Example 4.25 Synthesis of3-((3-fluorophenyl)ethynyl)-8-methoxy-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

To a solution of3-((3-fluorophenyl)ethynyl)-8-hydroxy-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one(0.2 g, 0.6 mmol, 1 equiv) in THF (15 mL) was added NaH (57.6 mg, 2.4mmol, 4 equiv) in portions. After stirring at rt for 1 h, the reactionmixture was quenched with water and extracted with ethyl acetate (3×50mL). The combined organic layers were dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified using silica gelchromatography to give the desired product. MS (ESI): 349 (M+H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.27-8.24 (d, J=8.46 Hz, 1H), 8.01 (s, 1H), 7.62-7.50(d, J=8.19 Hz, 1H), 7.37-7.35 (m, 2H), 7.30-7.28 (m, 1H), 7.14-7.09 (m,1H), 4.58-4.57 (m, 1H), 4.02-4.00 (m, 1H), 3.87-3.81 (m, 1H), 3.42 (s,3H), 3.33-3.20 (m, 2H), 2.26-2.15 (m, 2H). mGluR5 PAM EC₅₀: +++++. Foldshift at 10 μM: +.

Example 4.26 Synthesis of the HCl salt of8-methoxy-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.25. The product was then converted to thecorresponding HCl salt. MS (ESI): 332 (M+H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.93-8.91 (d, J=5.07 Hz, 1H), 8.65-8.59 (dt, J=7.59, 1.47 Hz, 1H),8.45-8.42 (d, J=8.28 Hz, 1H), 8.32-8.29 (d, J=7.98 Hz, 1H), 8.10-7.99(m, 3H), 4.57-4.52 (d, J=12.66 Hz, 1H), 4.15-4.12 (m, 1H), 3.96-3.90(dd, J=14.82, 3.24 Hz, 1H), 3.45 (s, 3H), 3.33 (s, 1H)?, 2.32-2.29 (m,1H), 2.23-2.17 (m, 1H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.

Example 4.27 Synthesis of the HCl salt of4-(pyridin-2-ylethynyl)-9,9a-dihydro-1H-cyclopropa[3,4]pyrrolo[2,1-b]quinazolin-7(1aH)-one

Example 4.27a Synthesis of 6-oxopiperidin-3-yl benzenesulfonate

The title compound was prepared according to the experimental procedureas described in Example 3.3a.

Example 4.27b Synthesis of3-bromo-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-8-yl4-bromobenzenesulfonate

A solution of 2-amino-4-bromobenzoic acid (1.4 g, 6.6 mmol, 1.1 equiv),6-oxopiperidin-3-yl 4-bromobenzenesulfonate (2 g, 6.0 mmol, 1 equiv),and phosphoryl trichloride (4 mL) in 1,4-dioxane (100 mL) was stirred at80° C. for two hours. After it was cooled to room temperature, thereaction mixture was diluted with water and extracted with ethyl acetate(3×100 mL). The combined organic layers were dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by silica gelchromatography to give the desired product.

Example 4.27c Synthesis of4-bromo-9,9a-dihydro-1H-cyclopropa[3,4]pyrrolo[2,1-b]quinazolin-7 (1aH)-one

A solution of3-bromo-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-8-yl4-bromobenzenesulfonate (0.5 g, 0.98 mmol, 1.1 equiv) and K₂CO₃ in MeOH(100 mL) was stirred at reflux for two hours. After it was cooled toroom temperature, the reaction mixture was diluted with water andextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over Na₂SO₄. After filtration and concentration, the residuewas purified by silica gel chromatography to give the desired product.

Example 4.27d Synthesis of the HCl salt of4-(pyridin-2-ylethynyl)-9,9a-dihydro-1H-cyclopropa[3,4]pyrrolo[2,1-b]quinazolin-7(1aH)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The compound was then converted to thecorresponding HCl salt. MS (ESI): 300 (M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ8.91-8.89 (d, J=5.22 Hz, 1H), 8.63-8.57 (t, J=7.94 Hz, 1H), 8.39-8.36(d, J=8.22 Hz, 1H), 8.29-8.27 (d, J=8.07 Hz, 1H), 8.08-8.02 (m, 2H),7.94-7.91 (d, J=8.27 Hz, 1H), 4.38-4.36 (m, 2H), 3.00-2.99 (m, 1H),2.67-2.67 (m, 1H), 1.79-1.75 (m, 1H), 1.19-1.16 (m, 1H). mGluR5 PAMEC₅₀: +++.

Example 4.28 Synthesis of3-((3-fluorophenyl)ethynyl)-8-methylene-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

Example 4.28a Synthesis of(3-bromo-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-8-yl)methylbenzenesulfonate

The title compound was prepared according to the experimental procedureas described in Example 2.2a.

Example 4.28b Synthesis of3-((3-fluorophenyl)ethynyl)-8-methylene-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 331 (M+H⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.27-8.24 (d, J=8.46 Hz, 1H), 8.01 (s, 1H), 7.62-7.50 (d,J=8.19 Hz, 1H), 7.37-7.35 (m, 2H), 7.30-7.28 (m, 1H), 7.14-7.09 (m, 1H),5.22 (s, 1H), 5.12 (s, 1H), 4.73 (s, 2H), 3.11-3.06 (t, J=6.60 Hz, 2H),2.72-2.68 (t, J=7.5 Hz, 2H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM:++.

Example 4.29 Synthesis of the HCl salt of8-methylene-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 3.3a, Example 2.2a, and Example 1.1. The productwas then converted to the corresponding HCl salt. MS (ESI): 314 (M+H⁺);¹H NMR (300 MHz, CDCl₃) δ 8.900-8.882 (d, J=5.553 Hz, 1H), 8.578-8.525(t, J=7.939 Hz, 1H), 8.461-8.433 (d, J=8.284 Hz, 1H), 8.264-8.237 (d,J=7.954 Hz, 1H), 8.064-7.977 (m, 3H), 5.357 (s, 1H), 5.285 (s, 1H),4.792 (s, 2H), 3.401-3.356 (t, J=6.783 Hz, 2H), 2.829-2.784 (t, J=6.768Hz, 2H).

Example 4.30 Synthesis of the HCl salt of8-(dimethylamino)-3-((3-fluorophenyl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

Example 4.30a Synthesis of3-bromo-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-8-ylbenzenesulfonate

The title compound was prepared according to the experimental procedureas described in Example 2.2a.

Example 4.30b Synthesis of3-bromo-8-(dimethylamino)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

A solution of3-bromo-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-8-ylbenzenesulfonate (0.15 g, 0.34 mmol, 1 equiv) and excess aq.dimethylamine in acetonitrile (6 mL) was stirred at 70° C. for 3 hours.After it was cooled to rt, the reaction mixture was diluted with waterand extracted with ethyl acetate (3×20 mL). The combined organic layerswere dried over Na₂SO₄. After filtration and concentration, the residuewas purified by silica gel chromatography to give the desired product.

Example 4.30c Synthesis of the HCl salt of8-(dimethylamino)-3-((3-fluorophenyl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 362 (M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ8.26-8.23 (d, J=8.28 Hz, 1H), 7.76 (s, 1H), 7.56-7.53 (dd, J=8.24, 1.46Hz, 1H), 7.37-7.34 (m, 2H), 7.27-7.23 (m, 1H), 7.13-7.06 (m, 1H),4.18-4.15 (m, 2H), 3.19-3.09 (m, 1H), 3.00-2.90 (m, 1H), 2.87-2.78 (m,1H), 2.38 (s, 6H), 2.22-2.12 (m, 1H), 2.02-1.92 (m, 1H). mGluR5 PAMEC₅₀: ++. Fold shift at 10 μM: +.

Example 4.31 Synthesis of3-((3-fluorophenyl)ethynyl)-8-(hydroxymethyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

Example 4.31a Synthesis of (9H-fluoren-9-yl)methyl(6-oxopiperidin-3-yl)methyl carbonate

The title compound was prepared according to the experimental procedureas described in Example 5.1a.

Example 4.31b Synthesis of (9H-fluoren-9-yl)methyl(3-bromo-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-8-yl)methylcarbonate

The title compound was prepared according to the experimental procedureas described in Example 2.2a.

Example 4.31c Synthesis of3-bromo-8-(hydroxymethyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 3.17b.

Example 4.31d Synthesis of3-((3-fluorophenyl)ethynyl)-8-(hydroxymethyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 349 (MH⁺)); ¹H NMR (300 MHz,CDCl₃) δ 8.26-8.22 (d, J=8.04 Hz, 1H), 7.77 (s, 1H), 7.56-7.54 (d,J=8.22 Hz, 1H), 7.36-7.31 (m, 2H), 7.28 (s, 1H), 7.13-7.10 (m, 1H),4.40-4.37 (dd, J=14.1, 5.1 Hz, 1H), 3.86-3.64 (m, 3H), 3.11-2.93 (m,2H), 2.34-2.24 (m, 1H), 2.20-2.11 (m, 1H), 1.80 (s, 1H), 1.73-1.67 (m,1H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: +++.

Example 4.32 Synthesis of the HCl salt of8-(hydroxymethyl)-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 332 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.87-8.85 (d, J=5.49 Hz, 1H), 8.50-8.42 (m, 2H), 8.20-8.17 (d, J=7.83Hz, 1H), 8.01-7.93 (m, 3H), 4.57-4.51 (m, 1H), 3.77-3.64 (m, 3H),3.39-3.36 (m, 2H), 2.30-2.28 (m, 1H), 2.17-2.14 (m, 1H), 1.83-1.79 (m,1H). mGluR5 PAM EC₅₀: ++.

Example 4.33 Synthesis of3-((3-fluorophenyl)ethynyl)-8-(methoxymethyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.25. MS (ESI): 346 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.27-8.24 (d, J=8.25 Hz, 1H), 7.76 (s, 1H), 7.56-7.53 (d,J=8.25 Hz, 1H), 7.37-7.34 (m, 2H), 7.27-7.26 (m, 1H), 7.13-7.07 (m, 1H),4.49-4.43 (m, 1H), 3.71-3.63 (m, 1H), 3.46-3.42 (m, 2H), 3.40 (s, 3H),3.12-2.98 (m, 2H), 2.35-2.29 (m, 1H), 2.14-2.04 (m, 1H), 1.74-1.60 (m,1H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 4.34 Synthesis of the HCl salt of8-(methoxymethyl)-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.25. The product was then converted to thecorresponding HCl salt. MS (ESI): 346 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ8.67-8.65 (d, J=4.77 Hz, 1H), 8.19-8.17 (d, J=8.22 Hz, 1H), 7.95-7.89(dt, J=7.8, 1.43 Hz, 1H), 7.83 (s, 1H), 7.77-7.74 (m, 1H), 7.70-7.67 (m,1H), 7.51-7.47 (m, 1H), 4.32-4.26 (dd, J=13.79, 5.15 Hz, 1H), 3.60-3.57(m, 1H), 3.42-3.37 (m, 2H), 3.29 (s, 3H), 3.07-2.99 (m, 2H), 2.32-2.27(m, 1H), 1.99-1.93 (m, 1H), 1.62-1.52 (m, 1H). mGluR5 PAM EC₅₀: ++++.Fold shift at 10 μM: +++.

Example 4.34a and Example 4.34b(S)-8-(methoxymethyl)-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-oneand(R)-8-(methoxymethyl)-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

Racemic8-(methoxymethyl)-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-onewas separated into the corresponding two single enantiomer compounds(S)-8-(methoxymethyl)-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-oneand(R)-8-(methoxymethyl)-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 3.0×25.0 cm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was isopropanol with 1% isopropylamine.Isocratic Method: 35% Co-solvent at 80 mL/min System Pressure: 100 bar.Column Temperature 25° C.

Faster moving enantiomer (fraction 1): Retention time=1.9 min 97.9% ee.mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++.Slower moving enantiomer (fraction 2): Retention time=2.2 min. 97.0% ee.mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.

Example 4.35 Synthesis of the HCl salt of3-((3-fluorophenyl)ethynyl)-8-((methylamino)methyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a, Example 3.3c, and Example 1.1. The productwas then converted to the corresponding HCl salt. MS (ESI): 362 (MH⁺);¹H NMR (300 MHz, DMSO-d⁶) δ 8.98-8.91 (broad, 2H), 8.19-8.16 (d, J=8.34Hz, 1H), 7.82 (dd, J=8.2, 1.4 Hz, 1H), 7.67-7.64 (dd, J=8.14, 1.38 Hz,1H), 7.56-7.47 (m, 1H), 7.37-7.31 (m, 1H), 4.43-4.36 (m, 1H), 3.60-3.52(m, 1H), 3.20-2.91 (m, 4H), 2.59-2.56 (m, 3H), 2.45-2.43 (m, 1H),2.12-2.05 (m, 1H), 1.74-1.64 (m, 1H).

Example 4.36 Synthesis of the HCl salt of8-((dimethylamino)methyl)-3-((3-fluorophenyl)ethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 3.3c and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 376 (MH⁺); ¹H NMR(300 MHz, DMSO-d⁶) δ 9.99-9.97 (s, 1H), 8.18-8.15 (d, J=8.16 Hz, 1H),7.79 (s, 1H), 7.65-7.62 (dd, J=8.25, 1.56 Hz, 1H), 7.56-7.46 (m, 1H),7.38-7.31 (m, 1H), 4.42-4.35 (m, 1H), 3.60-3.52 (m, 1H), 3.29-3.11 (m,2H), 3.06-2.97 (m, 2H), 2.82 (s, 3H), 2.78 (s, 3H), 2.56-2.51 (m, 1H),2.14-2.08 (m, 1H), 1.74-1.64 (m, 1H). mGluR5 PAM EC₅₀: +.

Example 4.37 Synthesis of the HCl salt of7-(hydroxymethyl)-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.1a, Example 2.2a, Example 3.17b, and Example1.1. The product was then converted to the corresponding HCl salt. MS(ESI): 332 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.88-8.87 (d, J=5.31 Hz,1H), 8.53-8.47 (t, J=7.94 Hz, 1H), 8.45-8.42 (d, J=8.25 Hz, 1H),8.23-8.20 (d, J=7.95 Hz, 1H), 8.02-7.95 (m, 3H), 4.55-4.47 (m, 1H),3.98-3.89 (m, 1H), 3.74-3.62 (m, 2H), 3.42-3.36 (m, 1H), 3.18-3.08 (m,1H), 2.34-2.26 (m, 2H), 1.87-1.84 (m, 1H). mGluR5 PAM EC₅₀: +++. Foldshift at 10 μM: ++.

Example 4.38 Synthesis of the HCl salt of7-(methoxymethyl)-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.25. The product was then converted to thecorresponding HCl salt. MS (ESI): 346 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.88-8.87 (d, J=5.34 Hz, 1H), 8.53-8.48 (t, J=7.95 Hz, 1H), 8.45-8.43(d, J=8.25 Hz, 1H), 8.23-8.20 (d, J=7.95 Hz, 1H), 8.02-7.96 (m, 3H),4.52-4.44 (m, 1H), 3.98-3.88 (m, 3H), 3.57-3.47 (m, 1H), 3.40 (s, 3H),3.18-3.09 (m, 1H), 2.47-2.42 (m, 1H), 2.32-2.55 (m, 1H), 1.90-1.83 (m,1H).

Example 4.39 Synthesis of the HCl salt of3-methyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-[1,4]oxazino[3,4-b]quinazolin-6(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 318 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.97-8.95 (d, J=5.58 Hz, 1H), 8.74-8.68 (dt, J=7.98,1.50 Hz, 1H), 8.46-8.43 (d, J=8.28 Hz, 1H), 8.39-8.37 (d, J=8.04 Hz,1H), 8.12-8.17 (dt, J=5.5, 1.2 Hz, 1H), 8.11-8.09 (s, 1H), 8.01-7.98(dd, J=8.30, 1.34 Hz, 1H), 5.22-5.02 (m, 2H), 4.21-4.15 (dd, J=6.97,1.48 Hz, 1H), 4.21-4.15 (m, 1H), 3.59-3.50 (m, 1H), 1.48-1.46 (d, J=6.0Hz, 3H).

Example 4.40 Synthesis of the HCl salt of3,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-[1,4]oxazino[3,4-b]quinazolin-6(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 332 (MH⁺); ¹H NMR(300 MHz, DMSO-d⁶) δ 8.68-8.67 (d, J=5.01 Hz, 1H), 8.21-8.18 (d, J=8.25Hz, 1H), 8.05-7.99 (t, J=7.76 Hz, 1H), 7.84-7.83 (m, 2H), 7.72-7.69 (d,J=8.25 Hz, 1H), 7.59-7.55 (m, 1H), 4.68 (s, 2H), 3.89 (s, 2H), 1.28 (s,6H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: +.

Example 4.41 Synthesis of8-fluoro-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

To a stirred solution of8-hydroxy-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one(100 mg, 0.315 mmol, 1 eq) in DCM was added excessDAST under N₂ at −78°C. After stirring at the same temperature for 3 hours, the reactionmixture was quenched with water (20 mL) and extracted with ethyl acetate(3×20 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure to give the desired product, whichwas purified by silica gel chromatography. MS (ESI): 320 (MH⁺); ¹H NMR(300 MHz, DMSO-d⁶) δ 8.65-8.65 (d, J=3.30 Hz, 1H), 8.17-8.14 (d, J=8.16Hz, 1H), 7.92-7.87 (t, J=7.5 Hz, 1H), 7.79 (s, 1H), 7.74-7.72 (d, J=7.71Hz, 1H), 7.67-7.64 (d, J=8.04 Hz, 1H), 7.48-7.47 (m, 1H), 5.50-5.34 (d,J=48.6 Hz, 1H), 4.62-4.52 (t, J=15.9 Hz, 1H), 3.93-3.79 (dd, J=38.1,15.3 Hz, 1H), 2.96-2.94 (m, 2H), 2.45-2.10 (m, 2H).

Example 4.42 Synthesis of8,8-difluoro-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.41. MS (ESI): 338 (MH⁺); ¹H NMR (300 MHz,DMSO-d⁶) δ 8.67-8.65 (d, J=4.02 Hz, 1H), 8.20-8.17 (d, J=8.10 Hz, 1H),7.95-7.90 (m, 1H), 7.84 (s, 1H), 7.77-7.69 (m, 2H), 7.51-7.47 (m, 1H),4.67-4.26 (m, 4H), 3.17-3.13 (m, 2H). mGluR5 PAM EC₅₀: ++++. Fold shiftat 10 μM: ++.

Example 4.43 Synthesis of the HCl salt of8-(pyridin-2-ylethynyl)-1,2,3,10b-tetrahydrocyclopropa[3,4]pyrido[2,1-b]quinazolin-5(1aH)-one

The title compound was prepared according to the experimental procedureas described in Example 3.3a, 4.27b, Example 4.27c, and Example 1.1. Theproduct was then converted to the corresponding HCl salt. MS (ESI): 314(MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.68-8.66 (d, J=4.71 Hz, 1H), 8.24-8.21(d, J=8.19 Hz, 1H), 7.84 (d, J=0.9 Hz, 1H), 7.76-7.71 (dt, J=7.8, 1.8Hz, 1H), 7.61-7.57 (m, 2H), 7.32-7.28 (m, 1H), 4.89-4.82 (dd, J=14.4,3.0 Hz, 1H), 3.15-3.10 (t, J=4.5 Hz, 1H), 2.37-2.30 (m, 2H), 2.10-1.92(m, 2H), 1.39-1.34 (m, 1H), 1.27-1.18 (m, 1H). mGluR5 PAM EC₅₀: ++++.Fold shift at 10 μM: ++.

Example 4.44 Synthesis of the HCl salt of6,6-difluoro-8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

Example 4.44a Synthesis of3-bromo-6,6-difluoro-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

To a solution of3-bromo-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11 (7H)-one(0.1 g, 0.327 mmol, 1 eq) in DMF (5 mL), Selectfluor (0.47 g, 1.31 mmol,4 eq) was added. The reaction mixture was heated to 90° C. and stirredfor 3 h. After it was cooled to room temperature, the reaction mixturewas diluted with water and extracted with ethyl acetate (3×50 mL), driedover Na₂SO₄. After filtration and concentration, 120 mg of the desiredproduct was obtained, which was directly used for the next step withoutfurther purification. MS (ESI): 343, 345 (MH⁺).

Example 4.44b Synthesis of the HCl salt of6,6-difluoro-8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 366 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ8.68-8.66 (d, J=4.14 Hz, 1H), 8.25-8.22 (d, J=8.22 Hz, 1H), 8.02 (s,1H), 7.96-7.91 (t, J=9.45 Hz, 1H), 7.82-7.76 (t, J=9.60 Hz, 2H),7.52-7.48 (dd, J=7.20, 5.40 Hz, 1H), 3.90 (s, 2H), 2.43-2.38 (d, J=17.1Hz, 2H), 1.11 (s, 6H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: +++.

Example 4.45 Synthesis of the HCl salt of8-hydroxy-8-methyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

Example 4.45a Synthesis of 3-bromo-6H-pyrido[2,1-b]quinazoline-8,11(7H,9H)-dione

To a solution of3-bromo-8-hydroxy-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (1g, 3.4 mmol, 1 equiv) in THF (30 mL) and DCM (20 mL) at 0° C. was addedDess-Martin reagent (2.9 g, 6.8 mmol, 2 equiv). The resulting mixturewas stirred at rt for 3 h. After that, 60 mL of aq. Na₂S₂O₃ was added.The mixture was extracted with ethyl acetate (3×100 mL), dried overNa₂SO₄. After filtration and concentration, 700 mg of the desiredproduct was obtained, which was directly used for the next step withoutfurther purification. MS (ESI): 293, 295 (MH⁺).

Example 4.45b Synthesis of3-bromo-8-hydroxy-8-methyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

To a solution of 3-bromo-6H-pyrido[2,1-b]quinazoline-8,11(7H,9H)-dione(0.04 g, 1.37 mmol, 1 equiv) in dry THF was added CH₃MgBr (0.27 mL, 2.74mmol, 2 equiv) dropwise at 0° C. The resulting mixture was stirred for 4h at 0° C. The reaction was quenched with saturated NH₄Cl, extractedwith EtOAc, and dried over Na₂SO₄. The organic extract was concentratedunder reduced pressure to give the desired product. MS (ESI): 309, 311(MH⁺).

Example 4.45c Synthesis of the HCl salt of8-hydroxy-8-methyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 332 (MH⁺). MS (ESI): 332 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.77-8.76 (d, J=4.68 Hz, 1H), 8.41-8.38 (d, J=8.64Hz, 1H), 8.27-8.22 (t, J=7.80 Hz, 1H), 8.02-7.99 (d, J=8.01 Hz, 1H),7.94-7.92 (m, 2H), 7.79-7.74 (t, J=6.00 Hz, 1H), 4.42-4.37 (d, J=15.01Hz, 1H), 3.69-3.64 (d, J=14.53 Hz, 1H), 3.48-3.45 (m, 1H), 3.28-3.21 (m,1H), 2.08-2.03 (m, 2H), 1.51 (s, 3H). mGluR5 PAM EC₅₀: ++. Fold shift at10 μM: ++.

Example 4.46 Synthesis of the HCl salt of8-methoxy-8-methyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

To a solution of8-hydroxy-8-methyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one(20 mg, 0.06 mmol, 1 equiv) and NaH (5.4 mg, 0.09 mmol, 1.5 equiv) indry THF was added CH₃I (25.5 mg, 0.18 mmol, 3 equiv) at rt. Theresulting mixture was heated at 60° C. and stirred for 2 hours. Aftercooling to rt, the reaction mixture was quenched with water andextracted with ethyl acetate, and dried over Na₂SO₄. The organic extractwas concentrated under reduced pressure and purified by columnchromatography to give 5 mg of the desired product. The product was thenconverted to the corresponding HCl salt. MS (ESI): 346 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.84-8.82 (d, J=5.19 Hz, 1H), 8.43-8.39 (m, 2H),8.15-8.12 (d, J=7.92 Hz, 1H), 7.97 (s, 1H), 7.94-7.90 (m, 2H), 4.67-4.61(dd, J=14.67, 2.31 Hz, 1H), 3.61-3.56 (d, J=14.71 Hz, 2H), 3.26 (s, 3H),3.24-3.08 (m, 1H), 2.38-2.26 (m, 1H), 2.08-1.95 (m, 1H), 1.48 (s, 3H).mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: +++.

Example 4.47 Synthesis of the HCl salt of6-fluoro-8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

Example 4.47a Synthesis of3-bromo-6-fluoro-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

To a solution of3-bromo-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11 (7H)-one(0.1 g, 0.327 mmol, 1 equiv) in DMF (5 mL), Selectfluor (0.12 g, 0.327mmol, 1 eq) was added. The reaction mixture was heated to 90° C. andstirred for 3 hours. After cooling to room temperature, the reactionmixture was diluted with water and extracted with ethyl acetate (3×50mL), dried over Na₂SO₄. After filtration and concentration, 80 mg of thedesired product was obtained, which was directly used for the next stepwithout further purification.

Example 4.47b Synthesis of the HCl salt of6-fluoro-8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 348 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ8.71-8.70 (d, J=4.59 Hz, 1H), 8.24-8.21 (d, J=8.22 Hz, 1H), 8.06-8.00(td, J=7.77, 1.51 Hz, 1H), 7.96 (s, 1H), 7.85-7.83 (d, J=7.80 Hz, 1H),7.78-7.75 (d, J=8.25 Hz, 1H), 7.59-7.56 (dd, J=6.60, 5.10 Hz, 1H),5.75-5.55 (dt, J=5.48, 5.52 Hz, 1H), 3.93-3.76 (dd, J=36.60, 13.50 Hz,2H), 2.25-1.95 (m, 2H), 1.08-1.04 (d, J=9.66 Hz, 6H). mGluR5 PAM EC₅₀:+++++. Fold shift at 10 μM: +++.

Example 4.48 Synthesis of the HCl salt of3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-6,9-ethanopyrido[2,1-b]quinazolin-11(7H)-one

Example 4.48a Synthesis of ethyl 4-aminocyclohexanecarboxylate

Ethyl 4-oxocyclohexanecarboxylate (3.0 g, 17.65 mmol) was dissolved in150 mL methanol saturated with ammonia at 0° C., and to the solution wasadded wet 10% Pd/C catalyst (4.0 g). The mixture was stirred at roomtemperature under hydrogen (1 atm) for about 36 h. Then the catalyst wasthen removed by filtration and the filtrate was concentrated to give thecrude product, which was purified by chromatography on silica gel togive 2.0 g of the desired product. MS (ESI): 172 (MH⁺).

Example 4.48b Synthesis of 2-azabicyclo[2.2.2]octan-3-one

A solution of ethyl 4-aminocyclohexanecarboxylate (0.6 g, 3.49 mmol),toluene (1 mL) in oil bath (170° C.) was heated for 2-3 h to dryness.After cooling to rt, the reaction mixture was diluted with water andextracted with ethyl acetate (3×30 mL). The combined organic layers weredried over Na₂SO₄. After filtration and concentration, 300 mg of thedesired product was obtained by column chromatography purification. MS(ESI): 126 (MH⁺).

Example 4.48c Synthesis of3-bromo-8,9-dihydro-6H-6,9-ethanopyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.27b. MS (ESI): 305, 307 (MH⁺).

Example 4.48d Synthesis of the HCl salt of3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-6,9-ethanopyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 328 (MH⁺). MS (ESI): 328 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.97-8.95 (d, J=5.34 Hz, 1H), 8.71-8.66 (t, J=7.97Hz, 1H), 8.51-8.48 (d, J=8.28 Hz, 1H), 8.38-8.35 (d, J=8.04 Hz, 1H),8.16-8.11 (t, J=6.30 Hz, 2H), 8.05-8.02 (d, J=8.28 Hz, 1H), 5.48 (s,1H), 3.53 (s, 1H), 2.22-2.08 (m, 4H), 1.95-1.88 (m, 4H). mGluR5 PAMEC₅₀: +++++. Fold shift at 10 μM: ++.

Example 4.49 Synthesis of the 2HCl salt of13a-methyl-8-(pyridin-2-ylethynyl)-2,3,13,13a-tetrahydro-1H-pyrrolo[1′,2′:4,5]pyrazino[2,1-b]quinazolin-11(5H)-one

Example 4.49a Synthesis of 1-tert-butyl 2-methyl2-methylpyrrolidine-1,2-dicarboxylate

To a solution of diisopropylamine (1.59 g, 15.7 mmol) in THF (10 mL) wasadded n-BuLi (7.54 mL, 2.5 M in n-hexane) dropwise at 0° C. Then thesolution was stirred at the same temperature for 30 min 1-tert-butyl2-methyl pyrrolidine-1,2-dicarboxylate (3.0 g, 13.0 mmol) was dissolvedin 50 mL THF and cooled to −78° C. To the solution was added preparedlithium diisopropylamide (15.7 mmol) dropwise. After the reactionmixture was kept at −78° C. for 3 h, MeI (1.6 mL, 25.7 mmol) was added.The mixture was allowed to warm to 0° C. and stirred for 2 h. Then thereaction mixture was quenched with water (30 mL) and extracted withEtOAc (3×50 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated under vacuum to give 2 g of the crude product. MS (ESI):244 (MH⁺).

Example 4.49b Synthesis of tert-butyl2-formyl-2-methylpyrrolidine-1-carboxylate

To a solution of 1-tert-butyl 2-methyl2-methylpyrrolidine-1,2-dicarboxylate (3.5 g, 14.3 mmol) in toluene at−78° C. was added DIBAL-H (17.6 mL, 30 mmol, 1.7 M) dropwise, whilemaintaining the reaction temperature below −65° C. The reaction wasstirred at −78° C. for 2 hr and then quenched with methanol (10 mL). Themixture was then diluted with ethyl acetate (50 mL), saturated NH₄Cl wasadded and the mixture was stirred vigorously for 20 min at roomtemperature. The two phases were then separated and the aqueous layerwas extracted with DCM (3×50 mL). The combined organics were then washedwith brine, dried over Na₂SO₄, concentrated in vacuo and purified bycolumn chromatography to give 3 g of the desired product.

Example 4.49c Synthesis of tert-butyl2-(aminomethyl)-2-methylpyrrolidine-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 4.48a. MS (ESI): 215 (MH⁺).

Example 4.49d Synthesis of tert-butyl2-((2-chloroacetamido)methyl)-2-methylpyrrolidine-1-carboxylate

A solution of tert-butyl2-(aminomethyl)-2-methylpyrrolidine-1-carboxylate (1.2 g), excess2-chloroacetyl chloride (2 mL) and diisopropyl ethyl amine (2 mL) in DCMwas stirred at room temperature for about 2 h. The reaction wasmonitored by LC-MS. After the solution was concentrated in vacuo, 0.7 gof the desired product was obtained by column chromatographypurification. MS (ESI): 291, 293 (MH⁺).

Example 4.49e Synthesis of2-chloro-N-((2-methylpyrrolidin-2-yl)methyl)acetamide

A solution of tert-butyl2-((2-chloroacetamido)methyl)-2-methylpyrrolidine-1-carboxylate (0.7 g,4.8 mmol) and TFA (3 mL) in DCM was stirred at room temperature forabout 3 h. Then the solution was concentrated to give 300 mg of thecrude product, which was directly used for the next step. MS (ESI): 191,193 (MH⁺).

Example 4.49f Synthesis of8a-methylhexahydropyrrolo[1,2-a]pyrazin-3(4H)-one

A solution of 2-chloro-N-((2-methylpyrrolidin-2-yl)methyl)acetamide(˜300 mg), K₂CO₃ (1.0 g, 7.2 mmol) and a catalytic amount of NaI inCH₃CN was stirred at 80° C. for about 3 h. The reaction was monitored byLC-MS. After cooling to room temperature, the suspension was dilutedwith water (30 mL) and extracted with DCM (8×100 mL). Then the combinedorganic layers were concentrated to give 120 mg of the desired product,which was directly used for the next step without further purification.MS (ESI): 155 (MH⁺).

Example 4.49g Synthesis of8-bromo-13a-methyl-2,3,13,13a-tetrahydro-1H-pyrrolo[1′,2′:4,5]pyrazino[2,1-b]quinazolin-11(5H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.27b. MS (ESI): 334, 336 (MH⁺).

Example 4.49h Synthesis of the 2HCl salt of13a-methyl-8-(pyridin-2-ylethynyl)-2,3,13,13a-tetrahydro-1H-pyrrolo[1′,2′:4,5]pyrazino[2,1-b]quinazolin-11(5H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 357 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.94-8.92 (d, J=5.6 Hz, 1H), 8.70-8.65 (t, J=8.0 Hz, 1H), 8.42-8.39 (d,J=8.2 Hz, 1H), 8.35-8.33 (d, J=7.9 Hz, 1H), 8.13-8.09 (m, 2H), 7.93-7.90(d, J=8.3 Hz, 1H), 4.80-4.75 (d, J=14.7 Hz, 1H), 4.67-4.62 (d, J=14.7Hz, 1H), 4.54-4.49 (d, J=14.7 Hz, 1H), 4.43-4.38 (d, J=14.7 Hz, 1H),3.95-3.91 (d, J=9.9 Hz, 1H), 3.27-3.24 (m, 1H), 2.17-2.13 (m, 4H), 1.62(s, 3H). mGluR5 PAM EC₅₀: +++.

Example 4.50 Synthesis of1-fluoro-8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

Example 4.50a Synthesis of(E)-N-(3-bromo-5-fluorophenyl)-2-(hydroxyimino)acetamide

A mixture of 3-bromo-5-fluoroaniline (4.0 g, 21.1 mmol, 1.0 equiv) inconc. HCl (10 mL) and water (100 mL) was heated until it became a clearsolution. 2,2,2-trichloroethane-1,1-diol (3.83 g, 23.2 mmol, 1.1 equiv)and Na₂SO₄ (22.5 g, 158.5 mmol, 7.3 equiv.) was pre-warmed to 50° C. andadded to the mixture. To the stirred mixture was then added an aqueoussolution of hydroxylammonium chloride (4.39 g, 63.2 mmol, 3.0 equiv)dropwise. The resulting mixture was refluxed for 1 h. After it wascooled to room temperature, the precipitate was filtered and washed withexcess water, dried under vacuum to provide 6.13 g of crude product,which was used into the next step without further purification. MS(ESI): 259, 261 (MH⁻).

Example 4.50b Synthesis of 6-bromo-4-fluoroindoline-2,3-dione

(E)-N-(3-bromo-5-fluorophenyl)-2-(hydroxyimino)acetamide (6.13 g, 23.6mmol) was slowly added to a solution of conc. H₂SO₄ (30 mL) in an icebath. The temperature of the reaction mixture was maintained below 50°C. After completion of the addition, the solution was heated to 90° C.for 1 h. After it was cooled to rt, the mixture was poured intoice-water and stirred vigorously for 1 h. The insoluble solid wasfiltered and washed with water, dried under vacuum to provide 7.4 g ofcrude product, which was used into the next step whitout furtherpurification. MS (ESI): 242, 244 (MH⁻).

Example 4.50c Synthesis of 2-amino-4-bromo-6-fluorobenzoic acid

To a solution of 6-bromo-4-fluoroindoline-2,3-dione (7.4 g, 31.8 mmol)in 1 M NaOH (100 mL) was added 38% H₂O₂ (13 mL) dropwise. The resultingsolution was stirred at rt for 2 h. The mixture was filtered and thefiltrate was acidified using hydrochloric acid (2 N) till pH becamearound 2. The precipitate was formed and filtered, washed with water,dried under vacuum to give 2.8 g of the desired product. MS (ESI): 232,234 (MH⁻).

Example 4.50d Synthesis of1-fluoro-8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound is prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 348 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.68-8.67 (d, J=4.8 Hz, 1H), 7.74-7.72 (d, J=4.5Hz, 2H), 7.47-7.43 (dd, J=9.0, 2.4 Hz, 1H), 7.31-7.24 (m, 2H), 3.83 (s,2H), 3.04-3.00 (t, J=6.9 Hz, 2H), 1.87-1.82 (t, J=6.9 Hz, 2H), 1.12 (s,6H).

Example 4.51 Synthesis of1-chloro-8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental proceduresdescribed in Example 4.50c, Example 2.2a and Example 1.1. MS (ESI): 364,366 (MH⁺).

Example 5.1 Synthesis of the HCl salt of9-((5-methylthiazol-2-yl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

Example 5.1a Synthesis of (9H-fluoren-9-yl)methyl3-oxopiperazine-1-carboxylate

To a solution of piperazin-2-one (2 g, 20 mmol, 1 equiv), Na₂CO₃ (4.2 g,40 mmol, 2 equiv) and water (20 mL) in 1,4-dioxane (60 mL) was addedFmoc-Cl (5.7 g, 22 mmol, 1.1 equiv) at 0° C. After the reaction mixturewas stirred at room temperature for 4 h, it was diluted with saturatedNaCl (200 mL). The solution was extracted with ethyl acetate (3×50 mL)and dried over Na₂SO₄. The combined organic layers were concentrated togive 6.7 g of the desired product, which was directly used for the nextstep without further purification. MS (ESI): 323 (MH⁺).

Example 5.1b (9H-fluoren-9-yl)methyl9-bromo-6-oxo-3,4-dihydro-1H-pyrazino[2,1-b]quinazoline-2(6H)-carboxylate

The title compound was prepared according to the experimental asdescribed in Example 2.2b. MS (ESI): 502 (MH⁺).

Example 5.1c Synthesis of9-bromo-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 3.17b. MS (ESI): 280/282 (MH⁺).

Example 5.1d Synthesis of9-((trimethylsilyl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

A flask was charged with9-bromo-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one (200 mg, 0.71mmol, 1 equiv), ethynyltrimethylsilane (206 mg, 2.1 mmol, 3 equiv),Pd(OAc)₂ (31.5 mg, 0.14 mmol, 0.2 equiv), PPh₃ (165 mg, 0.63 mmol, 0.9equiv), CuI (13 mg, 0.07 mmol, 0.1 equiv), Et₃N (353 mg, 3.5 mmol, 5equiv) and DMF (20 mL). A vacuum was applied and the reaction mixturewas back filled with nitrogen three times. The mixture was stirred at70° C. for 3.5 hours. After it was cooled to room temperature, thereaction mixture was diluted with H₂O and extracted with ethyl acetate(2×50 mL). The combined organic layers were washed with brine and driedover anhydrous sodium sulfate, then concentrated under reduced pressure.120 mg of desired product was obtained MS (ESI): 298 (MH⁺).

Example 5.1e Synthesis of9-ethynyl-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

To a solution of9-((trimethylsilyl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one(120 mg) in MeOH (50 mL) was added 1 N KOH (2 mL). The mixture wasstirred at room temperature for 1 h. Then the reaction mixture wasadjusted pH to 8 and extracted with ethyl acetate three times. Thecombined organic layers were dried over Na₂SO₄ and concentrated to givethe desired product (60 mg), which was purified by columnchromatography. MS (ESI): 226 (MH⁺).

Example 5.1f Synthesis of the HCl salt of94(5-methylthiazol-2-yl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 323 (MH⁺).

Example 5.2 Synthesis of2-methyl-9-((5-methylthiazol-2-yl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

Example 5.2a Synthesis of9-bromo-2-methyl-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

A solution of 9-bromo-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one(200 mg, 0.71 mmol, 1 equiv) and MeI (101 mg, 0.71 mmol, 1 equiv) inacetone (35 mL) was stirred at room temperature for 2 h. Then thereaction mixture was then concentrated and purified by columnchromatography to give 130 mg of the desired product. MS (ESI): 294/296(MH⁺).

Example 5.2b Synthesis of2-methyl-9-((trimethylsilyl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.1d. MS (ESI): 312 (MH⁺).

Example 5.2c Synthesis of9-ethynyl-2-methyl-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.1e. MS (ESI): 240 (MH⁺).

Example 5.2d Synthesis of the HCl salt of2-methyl-94(5-methylthiazol-2-yl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.1d. The product was then converted to thecorresponding HCl salt. MS (ESI): 337 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ8.27-8.24 (d, J=8.22 Hz, 1H), 7.81 (s, 1H), 7.61-7.56 (m, 2H), 4.11-4.07(t, J=5.12 Hz, 2H), 3.71 (s, 2H), 2.90-2.86 (t, J=5.72 Hz, 2H), 2.55 (s,3H), 2.50 (s, 3H).

Example 5.3 Synthesis of9-((4-fluorophenyl)ethynyl)-2-methyl-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 334 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.26-8.23 (d, J=8.28 Hz, 1H), 7.74 (s, 1H), 7.59-7.53 (m, 3H),7.12-7.06 (t, J=8.72 Hz, 2H), 4.11-4.08 (t, J=5.73 Hz, 2H), 3.71 (s,2H), 2.90-2.86 (t, J=5.67 Hz, 2H), 2.50 (s, 3H). mGluR5 PAM EC₅₀: ++++.Fold shift at 10 μM: +.

Example 5.4 Synthesis of9-((3-fluorophenyl)ethynyl)-2-methyl-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 334 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.27-8.24 (d, J=8.28 Hz, 1H), 7.76 (s, 1H), 7.58-7.54 (dd,J=8.24, J=1.49 Hz, 1H), 7.38-7.35 (m, 2H), 7.29-7.26 (m, 1H), 7.14-7.08(m, 1H), 4.12-4.08 (t, J=5.79 Hz, 2H), 3.71 (s, 2H), 2.90-2.86 (t,J=5.79 Hz, 2H), 2.50 (s, 3H). mGluR5 PAM EC₅₀: +++++.

Example 5.5 Synthesis of the HCl salt of2-methyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 317 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.89-8.87 (d, J=5.64 Hz, 1H), 8.61-8.55 (t, J=7.95 Hz, 1H), 8.38-8.35(d, J=8.4 Hz, 1H), 8.27-8.25 (d, J=8.28 Hz, 1H), 8.06-8.01 (m, 2H),7.86-7.83 (dd, J=8.24, 1.46 Hz, 1H), 4.65 (s, 2H), 4.38 (s, 2H), 4.38(t, J=5.8 Hz, 2H), 3.90 (t, J=5.8 Hz, 2H), 3.20 (s, 3H). mGluR5 PAMEC₅₀: ++.

Example 5.6 Synthesis of the HCl salt of2-(sec-butyl)-9-((3-fluorophenyl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

Example 5.6a Synthesis of9-bromo-2-sec-butyl-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

A solution of 9-bromo-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one(30 mg, 0.11 mmol) and excess 2-bromobutane in DMF (5 mL) was stirred at140° C. for 6 h. Then the reaction mixture was concentrated and purifiedby column chromatography to give the desired product. MS (ESI): 336, 338(MH⁺).

Example 5.6b Synthesis of the HCl salt of2-(sec-butyl)-9-((3-fluorophenyl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The compound was then converted to thecorresponding HCl salt. MS (ESI): 376 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ8.26-8.25 (d, J=8.61 Hz, 1H), 7.75 (s, 1H), 7.57-7.53 (dd, J=8.28, 1.53Hz, 1H), 7.26-7.25 (m, 1H), 7.13-7.06 (m, 1H), 7.37-7.34 (m, 2H),4.08-4.04 (m, 2H), 3.92-3.78 (q, 2H), 3.04-2.84 (m, 2H), 2.73-2.67 (m,1H), 1.53-1.35 (m, 1H), 1.11-1.08 (d, J=6.57 Hz, 3H), 0.99-1.00 (q, 3H),0.99-0.94 (m, 1H). mGluR5 PAM EC₅₀: ++.

Example 5.7 Synthesis of the HCl salt of2-allyl-9-((3-fluorophenyl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.6a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 360 (MH⁺); ¹H NMR(300 MHz, DMSO-d⁶) δ 8.20-8.17 (d, J=8.28 Hz, 1H), 7.80 (s, 1H),7.72-7.69 (d, J=7.95 Hz, 1H), 7.51-7.48 (m, 3H), 7.33-7.27 (m, 1H),5.98-5.92 (m, 1H), 5.66-5.59 (m, 2H), 4.45 (s, 2H), 4.17-4.18 (t, J=6.17Hz, 2H), 3.96-3.94 (d, J=6.66 Hz, 2H), 3.70-3.54 (m, 2H).

Example 5.8 Synthesis of the HCl salt of9-((3-fluorophenyl)ethynyl)-2-(2-hydroxyethyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.6a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 364 (MH⁺); ¹H NMR(300 MHz, DMSO-d⁶) δ 8.21-8.18 (d, J=8.10 Hz, 1H), 7.83 (s, 1H),7.72-7.69 (d, J=8.46 Hz, 1H), 7.54-7.47 (m, 3H), 7.38-7.35 (m, 1H),5.17-5.06 (broad, 6H), 4.61 (broad, 2H), 3.87 (broad, 2H), 3.44 (broad,2H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++.

Example 5.9 Synthesis of the HCl salt of9-((3-fluorophenyl)ethynyl)-2-(2-methoxyethyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.6a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 378 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.27-8.25 (d, J=8.19 Hz, 1H), 7.82 (s, 1H), 7.72-7.69(d, J=8.43 Hz, 1H), 7.49-7.41 (m, 2H), 7.36-7.33 (m, 1H), 7.23-7.17 (m,1H), 4.49-4.67 (d, J=4.80 Hz, 1H), 4.35 (broad, 3H), 3.94-3.86 (m, 4H),3.71-3.68 (m, 2H), 3.49-3.46 (s, 3H). mGluR5 PAM EC₅₀: ++. Fold shift at10 μM: ++.

Example 5.10 Synthesis of the HCl salt of2-benzyl-9-((3-fluorophenyl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.6a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 410 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.27-8.24 (d, J=8.31 Hz, 1H), 7.79 (s, 1H), 7.71-7.64(m, 3H), 7.61-7.57 (m, 3H), 7.47-7.40 (m, 2H), 7.36-7.32 (m, 1H),7.23-7.17 (m, 1H), 4.65 (s, 2H), 4.52-4.50 (m, 2H), 4.35 (m, 2H),3.91-3.87 (m, 2H). mGluR5 PAM EC₅₀: +.

Example 5.11 Synthesis of the HCl salt of2-butyl-9-((3-fluorophenyl)ethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.6a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 376 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.26-8.23 (d, J=8.28 Hz, 1H), 7.76 (s, 1H), 7.57-7.54(dd, J=8.13, 1.53 Hz, 1H), 7.38-7.34 (m, 2H), 7.32-7.31 (m, 1H),7.13-7.07 (m, 1H), 4.10-4.06 (t, J=5.73 Hz, 2H), 3.75 (s, 2H), 2.93-2.89(t, J=5.70 Hz, 2H), 2.58-2.53 (t, J=7.23 Hz, 2H), 1.56-1.54 (m, 2H),1.48-1.38 (m, 2H), 1.01-0.95 (t, J=5.7 Hz, 3H). mGluR5 PAM EC₅₀: ++.Fold shift at 10 μM: +++.

Example 5.12 Synthesis of the HCl salt of2-(6-oxo-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-2(6H)-yl)acetonitrile

The title compound was prepared according to the experimental procedureas described in Example 5.6a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 342 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.96-8.94 (dd, J=8.28, 1.41 Hz, 1H), 8.73-8.67 (t,J=7.98 Hz, 1H), 8.45-8.42 (d, J=8.31 Hz, 1H), 8.38-8.36 (d, J=7.98 Hz,1H), 8.16-8.10 (m, 2H), 7.80-7.99 (dd, J=8.28, 1.41 Hz, 1H), 4.23-4.19(m, 4H), 4.06 (s, 2H), 3.24-3.20 (t, J=5.60 Hz, 2H).

Example 5.13 Synthesis of the HCl salt of2-(9-((3-fluorophenyl)ethynyl)-6-oxo-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-2(6H)-yl)-N-methylacetamide

The title compound was prepared according to the experimental procedureas described in Example 5.6a and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 391 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.27-8.24 (d, J=8.28 Hz, 1H), 7.75 (s, 1H), 7.56-7.55(dd, J=8.24, 1.49 Hz, 1H), 7.38-7.35 (m, 2H), 7.27-7.26 (m, 1H),7.14-7.08 (m, 1H), 6.92 (m, 1H), 4.14-4.10 (t, J=5.70 Hz, 2H), 3.85 (s,2H), 3.32-3.28 (m, 2H), 3.08-3.04 (t, J=5.70 Hz, 2H), 2.91-2.89 (d,J=4.98 Hz, 2H).

Example 5.14 Synthesis of the 2HCl salt of2,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

Example 5.14a Synthesis of ethyl 2-(1-aminopropan-2-ylamino)acetate andethyl 2-(2-aminopropylamino)acetate

A solution of propane-1,2-diamine (2 g, 27 mmol, 1 equiv) and ethyl3-bromopropanoate (9.7 g, 54 mmol, 2 equiv) in EtOH (50 mL) was stirredat rt overnight. The reaction mixture was then concentrated under reducepressure to obtain the crude product, which was directly used for thenext step.

Example 5.14b Synthesis of 5-methylpiperazin-2-one and6-methylpiperazin-2-one

A solution of ethyl 2-(1-aminopropan-2-ylamino)acetate and ethyl2-(2-aminopropylamino)acetate (4 g, 22.8 mmol, 1 equiv) in DMF (50 mL)was stirred at reflux for 1 hour. After it was cooled to rt, thereaction mixture was diluted with water and extracted with DCM (3×100mL). The combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure to give the crude product, which was directlyused for the next step.

Example 5.14c Synthesis of (9H-fluoren-9-yl)methyl2-methyl-5-oxopiperazine-1-carboxylate and (9H-fluoren-9-yl)methyl3-methyl-5-oxopiperazine-1-carboxylate

A solution of 5-methylpiperazin-2-one and 6-methylpiperazin-2-one (3 g,26.3 mmol, 1 equiv), Na₂CO₃ (11.1 g, 105.2 mmol, 4 equiv) and Fmoc-Cl(13.6 g, 52.6 mmol, 2 equiv) in 1,4-dioxane (100 mL) and water wasstirred at rt over night. The reaction mixture was diluted with waterand extracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over Na₂SO₄. After filtration and concentration, the residuewas purified by silica gel chromatography to give the desired product.

Example 5.14d Synthesis of (9H-fluoren-9-yl)methyl9-bromo-3-methyl-6-oxo-3,4-dihydro-1H-pyrazino[2,1-b]quinazoline-2(6H)-carboxylate

A solution of 2-amino-4-bromobenzoic acid (2.8 g, 13.1 mmol, 1.1 equiv),(9H-fluoren-9-yl)methyl 2-methyl-5-oxopiperazine-1-carboxylate (4 g,11.9 mmol, 1 equiv), and phosphoryl trichloride (4 mL) in 1,4-dioxane(100 mL) was stirred at 80° C. for two hours. After it was cooled toroom temperature, the reaction mixture was quenched with water andextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over Na₂SO₄. After filtration and concentration, the residuewas purified by silica gel chromatography to give the desired product.

Example 5.14e Synthesis of9-bromo-3-methyl-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

A solution of (9H-fluoren-9-yl)methyl9-bromo-3-methyl-6-oxo-3,4-dihydro-1H-pyrazino[2,1-b]quinazoline-2(6H)-carboxylate(2 g, 3.9 mmol, 1 equiv) and piperidine (4 mL) in DCM (50 mL) wasstirred at room temperature overnight. The reaction mixture was thendiluted with water and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were dried over Na₂SO₄. After filtration andconcentration, the residue was purified by silica gel chromatography togive the desired product.

Example 5.14f Synthesis of9-bromo-2,3-dimethyl-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

To a solution of9-bromo-2,3-dimethyl-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one(0.2 g, 0.65 mmol, 1 equiv), NaH₃BCN (4.1 mg, 0.065 mmol, 0.1 equiv) andHOAc (0.05 mL) in methanol (5.0 mL) was added aq. formaldehyde (39 mg,1.3 mmol, 2 equiv) dropwise at room temperature. After stirring for afew minutes, the reaction mixture was diluted with water and extractedwith ethyl acetate (3×20 mL). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure to give the desiredproduct, which was purified by silica gel chromatography.

Example 5.14g Synthesis of the 2HCl salt of2,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 331 (M+H⁺); ¹H NMR (300 MHz,DMSO-d⁶+D₂O) δ 8.66-8.65 (d, J=4.74 Hz, 1H), 8.23-8.20 (d, J=8.25, 1H),8.02-7.97 (t, J=7.71 Hz, 1H), 7.87 (s, 1H), 7.82-7.74 (m, 2H), 7.57-7.53(m, 1H), 4.60 (s, 1H), 4.47-4.415 (dd, J=14.42, 3.49 Hz, 1H), 3.93-3.90(m, 3H), 2.96 (s. 3H), 1.46-1.45 (d, J=6.27 Hz, 3H). mGluR5 PAM EC₅₀:+++. Fold shift at 10 μM: +++.

Example 5.15 Synthesis of the 2HCl salt of2,4-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.14d, Example 5.14e, Example 5.14f, and Example1.1. The product was then converted to the corresponding 2HCl salt. MS(ESI): 331 (M+H⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ 8.69-8.68 (d, J=4.47 Hz,1H), 8.23-8.20 (d, J=8.25 Hz, 1H), 8.02-7.96 (t, J=7.8 Hz, 1H), 7.88 (s,1H), 7.82-7.80 (d, J=7.8 Hz, 1H), 7.76-7.73 (dd, J=8.25, 1.26 Hz, 1H),7.57-7.53 (m, 1H), 4.97 (broad, 1H), 4.61-4.56 (d, J=16.57 Hz, 1H),4.44-4.39 (d, J=16.53 Hz, 1H), 3.81 (broad, 1H), 3.69 (broad, 1H), 2.99(s, 3H), 1.59-1.56 (d, J=6.30 Hz, 3H). mGluR5 PAM EC₅₀: +++.

Example 5.16 Synthesis of the HCl salt of2,4,4-trimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.17b, Example 5.17d, Example 5.1a, Example5.14d, Example 3.17b, Example 1.1, and Example 1.21d. The product wasthen converted to the corresponding HCl salt. MS (ESI): 345 (MH⁺); ¹HNMR (300 MHz, CD₃OD) δ 8.82-8.80 (m, 1H), 8.57-8.52 (td, J=7.98 Hz, 1.55Hz, 1H), 8.24-8.20 (m, 2H), 8.01-7.87 (m, 1H), 7.73-7.72 (d, J=1.08 Hz,1H), 7.71-7.70 (dd, J=8.27 Hz, 1.48 Hz, 1H), 4.53 (s, 2H), 3.65 (s, 2H),3.08 (s, 3H), 1.80 (s, 6H).

Example 5.17 Synthesis of the 2HCl salt of3,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

Example 5.17a Synthesis of tert-butyl 2-amino-2-methylpropylcarbamate

To a stirred solution of 2-methylpropane-1,2-diamine (1.0 g, 11.3 mmol)in DCM (15 mL) at −55° C. was added a solution ofdi-tert-butyl-dicarbonate (2.5 g, 11.3 mmol) in DCM (15 mL) whilemaintaining the reaction temperature below −40° C. The reaction mixturewas stirred at −50° C. to −40° C. for 2 h, warmed to ambient temperatureover 2.5 h, and then stirred at ambient temperature for 1 h. Thesolution was then extracted with aqueous citric acid solution (10 wtpercent, 50 mL). The aqueous phase (pH 2-3) was made strongly alkaline(pH 14) with aqueous sodium hydroxide solution (50 wt percent, 5 mL) andextracted with DCM (5×25 mL). The combined organic layers were driedwith MgSO₄ and concentrated under reduced pressure to give the desiredproduct. MS (ESI): 189 (MH⁺).

Example 5.17b Synthesis of ethyl2-(1-(tert-butoxycarbonyl)-2-methylpropan-2-ylamino)acetate

A solution of tert-butyl 2-amino-2-methylpropylcarbamate (2.2 g, 11.7mmol) and ethyl bromoacetate (2.9 g, 17.6 mmol) in ethanol (40 mL) wasstirred at 60° C. for 48 h. After it was cooled to room temperature, themixture was concentrated and purified by column chromatography to givethe desired product. MS (ESI): 275 (MH⁺).

Example 5.17c Synthesis of ethyl2-(1-amino-2-methylpropan-2-ylamino)acetate

To a solution of ethyl2-(1-(tert-butoxycarbonyl)-2-methylpropan-2-ylamino) acetate (1.3 g, 4.7mmol) in DCM (30 mL) was added trifluoroacetic acid (15 mL). The mixturewas stirred at room temperature for 1 h. Then the reaction mixture wasconcentrated to give the desired product, which was directly used forthe next step. MS (ESI): 175 (MH⁺).

Example 5.17d Synthesis of 5,5-dimethylpiperazin-2-one

A solution of ethyl 2-(1-amino-2-methylpropan-2-ylamino) acetate (0.8 g,4.7 mmol) in DMF (20 mL) was stirred at reflux for 1 h. After it wascooled to room temperature, the mixture was concentrated to give thecrude product, which was directly used for the next step. MS (ESI): 129(MH⁺).

Example 5.17e Synthesis of9-bromo-3,3-dimethyl-1,2,3,4-tetrahydropyrazino-[2,1-b]quinazolin-6-one

The title compound was prepared according to the experimental procedureas described in Example 5.14d. MS (ESI): 308, 310 (MH⁺).

Example 5.17f Synthesis of the 2HCl salt of3,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-onehydrochloride

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 331 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.93-8.91 (d, J=5.78 Hz, 1H), 8.70-8.64 (t, J=7.98 Hz, 1H), 8.39-8.36(d, J=8.22 Hz, 1H), 8.34-8.31 (d, J=7.98 Hz, 1H), 8.13-8.08 (t, J=6.40Hz, 1H), 8.06 (s, 1H), 7.88-7.85 (dd, J=8.25, 1.50 Hz, 1H), 4.59 (s,2H), 4.25 (s, 2H), 1.61 (s, 6H). mGluR5 PAM EC₅₀: ++.

Example 5.18 Synthesis of the 2HCl salt of2,3,3-trimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.14f. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 345 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.92-8.90 (d, J=5.82 Hz, 1H), 8.67-8.62 (t, J=7.98 Hz, 1H), 8.38-8.35(d, J=8.22 Hz, 1H), 8.32-8.30 (d, J=8.01 Hz, 1H), 8.11-8.06 (t, J=7.62Hz, 1H), 8.04 (s, 1H), 7.87-7.84 (dd, J=8.25, 1.50 Hz, 1H), 4.69 (s,2H), 4.32 (s, 2H), 3.09 (s, 3H), 1.62 (s, 6H). mGluR5 PAM EC₅₀: +.

Example 5.19 Synthesis of the HCl salt of3-((3-fluorophenyl)ethynyl)-8,9,10,11,11a,12-hexahydropyrido[1′,2′:4,5]pyrazino[2,1-b]quinazolin-14(6H)-one

Example 5.19a Synthesis of tert-butyl2-((2-chloroacetamido)methyl)piperidine-1-carboxylate

To a solution of tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (2.0g, 9.3 mmol) and diisopropylethylamine (5 mL) in DCM (30 mL) was added2-chloroacetyl chloride (1.2 g, 10.6 mmol) dropwise at 0° C. The mixturewas stirred at room temperature overnight. Then the mixture was quenchedwith water (30 mL) and extracted with DCM (5×100 mL). The combinedorganic layers were dried over Na₂SO₄. After filtration andconcentration, the residue was used directly for the next reaction. MS(ESI): 291, 293 (MH⁺).

Example 5.19b Synthesis of7-bromo-2-(chloromethyl)-3-(piperidin-2-ylmethyl)quinazolin-4(3H)-one

A solution of tert-butyl2-((2-chloroacetamido)methyl)piperidine-1-carboxylate (590 mg, 2.02mmol) and POCl₃ (5 mL) was stirred at room temperature for 30 min. Then2-amino-4-bromobenzoic acid (442 mg, 1.94 mmol) was added to the mixtureand stirred for another 20 min After warming slowly to 100° C., themixture was maintained at 100° C. for 1.5 h. Then the reaction mixturewas poured into ice water, adjusted pH to 8 and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brineand dried over Na₂SO₄. After filtration and concentration, the crudeproduct was directly used for the next reaction. MS (ESI): 370, 372(MH⁺).

Example 5.19c Synthesis of3-bromo-8,9,10,11,11a,12-hexahydropyrido[1′,2′:4,5]pyrazino[2,1-b]quinazolin-14(6H)-one

A solution of7-bromo-2-(chloromethyl)-3-(piperidin-2-ylmethyl)quinazolin-4(3H)-oneand K₂CO₃ (1 g, 7.2 mmol) in CH₃CN was stirred at reflux for 1.5 h.After it was cooled to room temperature, the mixture was diluted withH₂O (30 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over Na₂SO₄, and the crude product waspurified by column chromatography to give the desired product. MS (ESI):334, 336 (MH⁺).

Example 5.19d Synthesis of the HCl salt of3-((3-fluorophenyl)ethynyl)-8,9,10,11,11a,12-hexahydropyrido[1′,2′:4,5]pyrazino[2,1-b]quinazolin-14 (6H)-one

A solution of3-bromo-8,9,10,11,11a,12-hexahydropyrido[1′,2′:4,5]pyrazino[2,1-b]quinazolin-14(6H)-one(105 mg, 0.31 mmol), 1-ethynyl-4-fluorobenzene (57 mg, 0.47 mmol),Pd(OAc)₂ (13 mg, 0.031 mmol), PPh₃ (39 mg, 0.15 mmol), CuI (8 mg, 0.031mmol), and Et₃N (0.2 mL) in DMF (7 mL) was stirred in a sealed tube at70° C. for 3.5 hours. After it was cooled to room temperature, thereaction mixture was diluted with H₂O and extracted with ethyl acetate(2×50 mL). The combined organic layers were washed with brine and driedover anhydrous sodium sulfate. After filtration and concentration, thecrude product was purified by silica gel chromatography to produce 45 mgof the desired product. The compound was then converted to thecorresponding HCl salt. MS (ESI): 374 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ8.21-8.18 (d, J=8.25 Hz, 1H), 7.82 (s, 1H), 7.74-7.68 (d, J=8.25 Hz,1H), 7.56-7.47 (m, 3H), 7.38-7.31 (m, 1H), 4.75-4.52 (m, 2H), 3.58(broad, 3H), 2.14-2.121 (m, 2H), 1.86-1.41 (m, 6H). mGluR5 PAM EC₅₀: +.

Example 5.20 Synthesis of the HCl salt of3-(pyridin-2-ylethynyl)-8,9,10,11,11a,12-hexahydropyrido[1′,2′:4,5]pyrazino[2,1-b]quinazolin-14(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.19d. The product was then converted to thecorresponding HCl salt. MS (ESI): 357 (MH⁺); δ 8.93-8.91 (d, J=5.16 Hz,1H), 8.70-8.64 (dt, J=7.98, 1.44 Hz, 1H), 8.37-8.32 (m, 2H), 8.13-8.08(m, 1H), 8.04-8.03 (d, J=1.08 Hz, 1H), 7.87-7.83 (m, J=8.28, 1.44 Hz,1H), 4.80-4.54 (m, 3H), 3.82 (broad, 3H), 3.27-3.19 (m, 1H), 2.33-2.29(m, 1H), 2.12-1.93 (m, 3H), 1.84-1.72 (m, 2H). mGluR5 PAM EC₅₀: +.

Example 5.21 Synthesis of the HCl salt of8-((3-fluorophenyl)ethynyl)-2,3,13,13a-tetrahydro-1H-pyrrolo[1′,2′:4,5]pyrazino[2,1-b]quinazolin-11(5H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.19. The product was then converted to thecorresponding HCl salt. MS (ESI): 360 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ8.28-8.25 (d, J=8.26 Hz, 1H), 7.78 (s, 1H), 7.58-7.55 (dd, J=6.00, 1.57Hz, 1H), 7.38-7.32 (m, 2H), 7.28-7.26 (m, 1H), 7.13-7.07 (m, 1H),4.57-4.51 (dd, J=13.64, 3.80 Hz, 1H), 4.30-4.25 (d, J=16.51 Hz, 1H),3.59-3.50 (m, 2H), 3.29-3.23 (t, J=6.30 Hz, 1H), 2.65-2.59 (m, 1H),2.43-2.34 (m, 1H), 2.24-2.13 (m, 1H), 2.04-1.89 (m, 2H), 1.76 (m, 1H).mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 5.22 Synthesis of the HCl salt of8-(pyridin-2-ylethynyl)-2,3,13,13a-tetrahydro-1H-pyrrolo[1′,2′:4,5]pyrazino[2,1-b]quinazolin-11(5H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.19d. The product was then converted to thecorresponding HCl salt. MS (ESI): 343 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.97-8.92 (d, J=6.51 Hz, 1H), 8.71-8.63 (t, J=8.03 Hz, 1H), 8.44-8.32(d, J=6.51 Hz, 2H), 8.14-8.03 (m, 2H), 7.92-7.89 (dd, J=8.22, 1.44 Hz,1H), 4.86-4.80 (m, 2H), 4.76-4.71 (d, J=14.58 Hz, 1H), 4.60-4.56 (d,J=14.70 Hz, 1H), 4.33-4.29 (m, 2H), 3.92-3.91 (m, 1H), 2.49-2.43 (m,1H), 2.30-2.22 (m, 1H), 2.13-2.1.90 (m, 2H). mGluR5 PAM EC₅₀: +++. Foldshift at 10 μM: +++.

Example 5.23 Synthesis of the HCl salt of(S)-8-(pyridin-2-ylethynyl)-2,3,13,13a-tetrahydro-1H-pyrrolo[1′,2′:4,5]pyrazino[2,1-b]quinazolin-11(5H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.19. The product was then converted to thecorresponding HCl salt. MS (ESI): 321 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.94-8.92 (dd, J=5.83, 0.76 Hz, 1H), 8.71-8.65 (t, J=7.98 Hz, 1H),8.40-8.33 (m, 2H), 8.14-8.09 (m, 2H), 7.91-7.88 (dd, J=8.25, 1.50 Hz,1H), 4.86-4.80 (m, 2H), 4.76-4.71 (m, 1H), 4.60-4.55 (m, 1H), 4.32-4.29(d, J=9.45 Hz, 2H), 3.91 (s, 1H), 2.49-2.45 (m, 1H), 2.25-2.20 (m, 1H),2.04-1.96 (m, 2H). mGluR5 PAM EC₅₀: +++.

Example 5.24 Synthesis of the HCl salt of8-(pyridin-3-ylethynyl)-2,3,13,13a-tetrahydro-1H-pyrrolo[1′,2′:4,5]pyrazino[2,1-b]quinazolin-11(5H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.19d. The product was then converted to thecorresponding HCl salt. MS (ESI): 321 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ9.22 (s, 1H), 8.94-8.92 (d, J=5.79 Hz, 1H), 8.87-8.84 (d, J=8.37 Hz,1H), 8.38-8.34 (d, J=8.16 Hz, 1H), 8.22-8.17 (m, 2H), 8.03 (s, 1H),7.85-7.82 (d, J=8.27 Hz, 1H), 4.85-4.80 (m, 2H), 4.76-4.71 (m, 1H),4.62-4.60 (d, J=14.77 Hz, 1H), 4.37-4.29 (m, 2H), 4.39-4.38 (m, 1H),2.49-2.41 (m, 1H), 2.28-2.22 (m, 1H), 2.10-1.96 (m, 2H). mGluR5 PAMEC₅₀: +++.

Example 5.25 Synthesis of the HCl salt of11-((3-fluorophenyl)ethynyl)-2,3,5,6-tetrahydro-1H-pyrrolo[2′,1′:3,4]pyrazino[2,1-b]quinazolin-8(13bH)-one

Example 5.25a Synthesis of 2-amino-4-bromobenzamide

A solution of 2-amino-4-bromobenzoic acid (1 g, 4.63 mmol), NH₄Cl (1.8g, 32.41 mmol), TBTU (1.5 g, 4.63 mmol) and diisopropylethylamine (1.2g, 9.26 mmol) in DMF (30 mL) was stirred at room temperature overnight.Then the mixture was adjusted to pH 8.0 with saturated Na₂CO₃ andextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over Na₂SO₄ and concentrated to give the desired yellow product.MS (ESI): 215, 217 (MH⁺).

Example 5.25b Synthesis of (9H-fluoren-9-yl)methyl2-(chlorocarbonyl)pyrrolidine-1-carboxylate

To a solution of1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (1.2mg, 3.6 mmol) and 2 drops DMF in DCM was added oxalyl dichloride (2 g,15.9 mmol), resulting in bubbling of the solution. After the solutionstopped bubbling, the reaction solution was concentrated to give thecrude product, which was directly used for the next step.

Example 5.25c Synthesis of (9H-fluoren-9-yl)methyl2-(5-bromo-2-carbamoylphenylcarbamoyl)pyrrolidine-1-carboxylate

A solution of (9H-fluoren-9-yl)methyl2-(chlorocarbonyl)pyrrolidine-1-carboxylate (600 mg, 1.8 mmol),2-amino-4-bromobenzamide (400 mg, 1.8 mmol), and Et₃N (2 mL) in THF wasstirred at room temperature. The reaction was monitored by TLC. Afterdiluting with H₂O (50 mL), the mixture was extracted with ethyl acetate(3×100 mL). The organic layers were dried over Na₂SO₄ and concentratedto give yellow residue, which was purified by column chromatography. MS(ESI): 534, 536 (MH⁺)

Example 5.25d Synthesis of (9H-fluoren-9-yl)methyl2-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate

A solution of(9H-fluoren-9-yl)methyl-2-(5-bromo-2-carbamoylphenylcarbamoyl)pyrrolidine-1-carboxylate (0.55 g, 0.94 mmol) in excess SOCl₂ wasstirred at room temperature. After pouring into ice water, the mixturewas adjusted to pH 7.0, extracted with ethyl acetate (3×100 mL) andconcentrated to give the crude product. 152 mg of the desired productwas obtained by column chromatography. MS (ESI): 516, 518 (MH⁺)

Example 5.25e Synthesis of7-bromo-2-(pyrrolidin-2-yl)quinazolin-4(3H)-one

A solution of(9H-fluoren-9-yl)methyl-2-(7-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (305 mg, 1.04 mmol) and piperidine (2 mL) inCH₃CN was stirred at room temperature for 2 h. The mixture was dilutedwith H₂O (30 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine and dried over Na₂SO₄.After filtration and concentration, the crude product was purified bycolumn chromatography to give 162 mg of the desired product. MS (ESI):294, 296 (MH⁺)

Example 5.25f Synthesis of11-bromo-2,3,5,6-tetrahydro-1H-pyrrolo[2′,1′:3,4]pyrazino[2,1-b]quinazolin-8(13bH)-one

A solution of 7-bromo-2-(pyrrolidin-2-yl)quinazolin-4(3H)-one (158 mg,0.49 mmol), K₂CO₃ (0.5 g, 3.6 mmol), a catalytic amount of NaI, and1-bromo-2-chloroethane (70 mg, 0.49 mmol) in CH₃CN was stirred at 80° C.overnight. After dilution with H₂O (30 mL), the mixture was extractedwith ethyl acetate (3×100 mL). Then the combined organic layers weredried over Na₂SO₄ and concentrated to give crude product. After purifiedby column chromatography, 46 mg of the desired product was obtained. MS(ESI): 320, 322 (MH⁺)

Example 5.25g Synthesis of the HCl salt of11-((3-fluorophenyl)ethynyl)-2,3,5,6-tetrahydro-1H-pyrrolo[2′,1′:3,4]pyrazino[2,1-b]quinazolin-8(13bH)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 360 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ7.92-7.89 (d, J=8.01 Hz, 1H), 7.83-7.82 (d, J=1.44 Hz, 1H), 7.76-7.73(dd, J=8.07, 1.50 Hz, 1H), 7.50-7.39 (m, 2H), 7.35-7.31 (m, 1H),7.25-7.18 (m, 1H) 4.69-4.64 (t, J=8.58 Hz, 1H), 4.24-4.06 (m, 2H),4.02-3.84 (m, 2H), 3.81-3.74 (m, 1H), 3.64-3.55 (m, 1H), 2.69-2.60 (m,1H), 2.57-2.50 (m, 1H), 2.35-2.28 (m, 1H), 2.22-2.12 (m, 1H).

Example 5.26 Synthesis of3,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-one

Example 5.26a Synthesis of (E)-methyl4-bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzoate

A mixture of 4,5-dichloro-1,2,3-dithiazol-1-ium chloride (1.9 g, 9.1mmol) and methyl 2-amino-4-bromobenzoate (1.0 g, 4.3 mmol) in DCM (10mL) was stirred for 48 h at room temperature. The solvent was evaporatedto give the crude compound, which was purified by column chromatographyon silica gel to give 350 mg of the desired product. MS (ESI): 367(MH⁺).

Example 5.26b Synthesis of9-bromo-3,3-dimethyl-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-one

A mixture of(E)-methyl-4-bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzoate(0.1 g, 0.27 mmol) and 2,2-dimethylpropane-1,3-diamine (28 mg, 0.27mmol) in dry THF was stirred for 2 h at room temperature, then thesolvent was evaporated to give the crude product, which was purified bycolumn chromatography to give 80 mg of the title compound. MS (ESI):308, 310 (MH⁺).

Example 5.26c Synthesis of3,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-one

The title compound was prepared according to the experimental proceduredescribed in Example 1.1. MS (ESI): 331 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ8.67-8.65 (d, J=4.2 Hz, 1H), 8.11-8.08 (d, J=8.2 Hz, 1H), 7.75-7.69 (td,J=7.5, 1.5 Hz, 1H), 7.62-7.57 (d, J=7.8 Hz, 1H), 7.48 (s, 1H), 7.34-7.31(m, 2H), 3.81 (s, 2H), 3.19 (s, 2H), 1.16 (s, 6H). mGluR5 PAM EC₅₀:+++++. Fold shift at 10 μM: +++.

Example 5.27 Synthesis of1,3,3-trimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-one

A mixture of3,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrimido[2,1-b]quinazolin-6(2H)-one(30 mg, 0.09 mmol), NaH (14 mg, 0.36 mmol) and MeI (28 mg, 0.2 mmol) indry THF was stirred for 24 h at room temperature. Then the solvent wasevaporated to give the crude product, which was purified by columnchromatography to give 3 mg of the title compound. MS (ESI): 345 (MH⁺).¹H NMR (300 MHz, CDCl₃) δ 8.66-8.65 (d, J=4.8 Hz, 1H), 8.08-8.05 (d,J=8.2 Hz, 1H), 7.75-7.69 (td, J=7.8, 1.8 Hz, 1H), 7.60-7.55 (m, 2H),7.31-7.30 (m, 2H), 3.82 (s, 2H), 3.28 (s, 3H), 3.18 (s, 2H), 1.13 (s,6H).

Example 6.1 Synthesis of8-((4-fluorophenyl)ethynyl)-4,5-dihydro-1H-[1,4]oxazepino[5,4-b]quinazolin-11(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 335 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.25-8.22 (d, J=8.2 Hz, 1H), 7.76 (s, 1H),7.59-7.55 (m, 3H), 7.13-7.06 (d, J=7.8 Hz, 2H), 4.60-4.58 (m, 2H),4.01-3.98 (m, 2H), 3.92-3.89 (m, 2H), 3.32-3.29 (m, 2H). mGluR5 PAMEC₅₀: +++++. Fold shift at 10 μM: ++.

Example 6.2 Synthesis of the HCl salt of8-(pyridin-2-ylethynyl)-4,5-dihydro-1H-[1,4]oxazepino[5,4-b]quinazolin-11(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 318 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.72-8.70 (d, J=4.8 Hz, 1H), 8.23-8.20 (d, J=8.21 Hz, 1H), 8.05-7.98 (m,2H), 7.86-7.84 (d, J=7.8 Hz, 1H), 7.79-7.76 (d, J=8.21 Hz, 1H),7.60-7.56 (m, 1H), 4.53-4.51 (m, 2H), 3.94-3.83 (m, 4H), 3.43-3.40 (m,2H).

Example 6.3 Synthesis of3-((4-ethylphenyl)ethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 343 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.11-8.09 (d, J=8.22 Hz, 1H), 7.69 (s, 1H),7.59-7.52 (m, 3H), 7.32-7.29 (d, J=8.16 Hz, 2H), 4.34-4.31 (m, 2H), 3.05(broad, 2H), 2.69-2.62 (m, 2H), 1.75-1.72 (m, 6H), 1.22-1.17 (t, J=7.56Hz, 3H). mGluR5 PAM EC₅₀: ++.

Example 6.4 Synthesis of3-(phenylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 315 (MH⁺). ¹H NMR (300 MHz,CDCl₃) δ 8.24-8.22 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.62-7.56 (m, 3H),7.46-7.38 (m, 3H), 4.42-4.39 (m, 2H), 3.11-3.07 (m, 2H), 1.89-1.85 (m,6H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 6.5 Synthesis of the HCl salt of3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 316 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.95-8.93 (d, J=5.61 Hz, 1H), 8.69-8.63 (t, J=7.98 Hz, 1H), 8.47-8.44(d, J=8.28 Hz, 1H), 8.36-8.33 (d, J=8.01 Hz, 1H), 8.14-8.09 (m, 2H),8.05-8.02 (d, J=8.30 Hz, 1H), 4.59-4.56 (m, 2H), 3.44-3.40 (m, 2H),2.06-1.90 (m, 6H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 6.6 Synthesis of3-((4-fluorophenyl)ethynyl)-8-methyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 347 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.24-8.214 (d, J=8.22 Hz, 1H), 7.76 (s, 1H),7.59-7.52 (m, 3H), 7.12-7.06 (t, J=8.7 Hz, 2H), 5.21-5.15 (m, 1H),3.64-3.55 (m, 1H), 3.15-3.00 (m, 2H), 2.13-2.08 (m, 2H), 1.95-1.81 (m,1H), 1.46-1.20 (m, 2H), 1.02-1.00 (d, J=6.57 Hz, 3H). mGluR5 PAM EC₅₀:+++++. Fold shift at 10 μM: ++.

Example 6.7 Synthesis of3-((3-fluorophenyl)ethynyl)-8-methyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental asdescribed in Example 1.1. MS (ESI): 347 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ8.29-8.24 (d, J=8.22 Hz, 1H), 7.76 (s, 1H), 7.55-7.53 (d, J=8.21 Hz,1H), 7.36-7.25 (m, 3H), 7.12-7.06 (m, 1H), 5.21-5.19 (m, 1H), 3.64-3.55(m, 1H), 3.15-3.00 (m, 2H), 2.13-2.08 (m, 2H), 1.95-1.81 (m, 1H),1.46-1.20 (m, 2H), 1.02-1.00 (d, J=6.57 Hz, 3H). mGluR5 PAM EC₅₀: +++++.Fold shift at 10 μM: ++.

Example 6.8 Synthesis of8-methyl-3-((5-methylthiazol-2-yl)ethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Example 6.8a Synthesis of8-methyl-3-((trimethylsilyl)ethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.1d.

Example 6.8b Synthesis of3-ethynyl-8-methyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.1e.

Example 6.8c Synthesis of8-methyl-3-((5-methylthiazol-2-yl)ethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 350 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.26-8.23 (d, J=8.1 Hz, 1H), 7.81 (s, 1H), 7.62-7.56 (m, 2H),5.22-5.15 (m, 1H), 3.65-3.56 (m, 1H), 3.16-3.00 (m, 2H), 2.55 (s, 3H),2.14-2.08 (m, 2H), 1.96-1.86 (m, 1H), 1.47-1.33 (m, 1H), 1.29-1.23 (m,1H), 1.02-1.00 (d, J=6.6 Hz, 3H). mGluR5 PAM EC₅₀: ++++. Fold shift at10 μM: ++.

Example 6.9 Synthesis of the HCl salt of8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 330 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.69-8.67 (d, J=4.3 Hz, 1H), 8.22-8.19 (d, J=8.2 Hz, 1H), 7.99-7.94 (m,2H), 7.82-7.76 (m, 2H), 7.56-7.51 (m, 1H), 4.95-4.88 (dd, J=14.40, 6.9Hz, 1H), 3.84-3.76 (m, 1H), 3.28-3.24 (m, 2H), 1.98-1.91 (m, 3H),1.41-1.21 (m, 2H), 0.93-0.91 (d, J=6.3 Hz, 3H). mGluR5 PAM EC₅₀: +++++.Fold shift at 10 μM: +++.

Example 6.10 and Example 6.11 Separation of(S)-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Racemic8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-onewas separated into the corresponding two single enantiomer compounds(S)-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 3.0×25.0 cm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was methanol:isopropanol (1:1) with 1%isopropylamine. Isocratic Method: 45% Co-solvent at 80 mL/min SystemPressure: 100 bar. Column Temperature 25° C.

Faster moving enantiomer (fraction 1): Retention time=1.9 min 98.2% ee.mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: +++.Slower moving enantiomer (fraction 2): Retention time=3.5 min. 99.8% ee.mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: +++.

Example 6.12 Synthesis of8-ethyl-3-((4-fluorophenyl)ethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.11a, Example 4.11b, Example 2.2a, and Example1.1. MS (ESI): 361 (M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.21 (d,J=8.10 Hz, 1H), 7.75 (s, 1H), 7.59-7.52 (m, 3H), 7.12-7.06 (m, 2H),5.24-5.16 (dd, J=14.40, 6.60 Hz, 1H), 3.64-3.55 (t, J=14.70 Hz, 1H),3.13-3.03 (m, 2H), 2.21-2.13 (m, 2H), 1.70-1.60 (m, 1H), 1.44-1.19 (m,4H), 0.97-0.92 (t, J=7.43 Hz, 3H). mGluR5 PAM EC₅₀: +++++. Fold shift at10 μM: ++.

Example 6.13 Synthesis of3-((4-fluorophenyl)ethynyl)-8-propyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.11a, Example 4.11b, Example 2.2a, and Example1.1. MS (ESI): 375 (M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.21 (d,J=8.28 Hz, 1H), 7.75 (s, 1H), 7.59-7.52 (m, 3H), 7.18-7.06 (m, 2H),5.23-5.15 (m, 1H), 3.64-3.56 (m, 1H), 3.17-2.99 (m, 2H), 2.20-2.12 (m,2H), 1.78-1.71 (m, 1H), 1.44-1.22 (m, 6H), 0.95-0.88 (t, J=7.04 Hz, 3H).mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +.

Example 6.14 Synthesis of3-((3-fluorophenyl)ethynyl)-6,7,9,10-tetrahydroazepino[2,1-b]quinazoline-8,12-dione

Example 6.14a Synthesis of3-bromo-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]dioxolan]-12(7H)-one

The title compound was prepared according to the experimental asdescribed in Example 2.2a.

Example 6.14b Synthesis of3-bromo-6,7,9,10-tetrahydroazepino[2,1-b]quinazoline-8,12-dione

A solution of3-bromo-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]dioxolan]-12(7H)-one(0.5 g, 1.43 mmol) and 4N HCl (4 mL) in THF (20 mL) was heated at refluxfor 4 h. After it was cooled to rt, the reaction mixture was quenchedwith aq. Na₂CO₃ and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over Na₂SO₄. After filtration andconcentration, the residue was purified by silica gel chromatography togive the desired product.

Example 6.14c Synthesis of3-((3-fluorophenyl)ethynyl)-6,7,9,10-tetrahydroazepino[2,1-b]quinazoline-8,12-dione

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 347 (M+H⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.28-8.26 (d, J=8.19 Hz, 1H), 7.80 (s, 1H) 7.63-7.60 (dd,J=8.24, 1.55 Hz, 1H), 7.39-7.35 (m, 2H), 7.31-7.30 (m, 1H), 7.15-7.09(m, 1H), 4.60-4.56 (m, 2H), 3.30-3.26 (m, 2H), 2.89-2.79 (m, 4H). mGluR5PAM EC₅₀: ++++. Fold shift at 10 μM: +++.

Example 6.15 Synthesis of3-((3-fluorophenyl)ethynyl)-8-hydroxy-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.23. MS (ESI): 349 (M+H⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.25-8.22 (d, J=8.25 Hz, 1H), 7.76 (s, 1H) 7.58-7.55 (dd,J=8.24, 1.52 Hz, 1H), 7.38-7.35 (m, 2H), 7.30-7.29 (m, 1H), 7.14-7.07(m, 1H), 4.49-4.48 (m, 2H), 4.24-4.20 (m, 1H), 3.50-3.41 (m, 1H),2.94-2.86 (m, 1H), 2.09-2.06 (m, 4H). mGluR5 PAM EC₅₀: +++++. Fold shiftat 10 μM: ++.

Example 6.16 Synthesis of the HCl salt of8-hydroxy-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1 and Example 4.23. The product was thenconverted to the corresponding HCl salt. MS (ESI): 332 (M+H⁺); ¹H NMR(300 MHz, DMSO-d⁶) δ 8.69-8.67 (d, J=4.71 Hz, 1H), 8.21-8.18 (d, J=8.25Hz, 1H), 7.99-7.93 (m, 2H), 7.81-7.74 (m, 2H), 7.55-7.50 (m, 1H),4.51-4.38 (m, 2H), 3.95-3.90 (m, 1H), 3.43-3.35 (m, 1H), 3.06-2.98 (m,1H), 2.04-1.68 (m, 4H). mGluR5 PAM EC₅₀: +++.

Example 6.17 Synthesis of the HCl salt of8-hydroxy-3-(pyridin-3-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.23 and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 332 (M+H⁺); ¹H NMR(300 MHz, DMSO-d⁶) δ 8.92 (s, 1H), 8.70-8.68 (m, 1H), 8.21-8.16 (m, 2H),7.87 (s, 1H), 7.72-7.69 (dd, J=8.24, 1.52 Hz, 1H), 7.63-7.58 (m, 1H),4.52-4.38 (m, 1H), 4.32-4.14 (m, 2H), 3.38-3.29 (m, 1H), 2.99-2.91 (m,1H), 2.02-1.66 (m, 4H). mGluR5 PAM EC₅₀: ++.

Example 6.18 Synthesis of3-((3-fluorophenyl)ethynyl)-8-methoxy-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.25. MS (ESI): 363 (M+H⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.25-8.22 (d, J=8.25 Hz, 1H), 7.76 (s, 1H) 7.57-7.54 (d, J=8.07Hz, 1H), 7.40-7.32 (m, 2H), 7.28-7.26 (m, 1H), 7.13-7.06 (m, 1H),4.68-4.64 (m, 1H), 4.27-4.19 (m, 1H), 3.65-3.64 (m, 1H), 3.50-3.36 (m,4H), 2.89-2.81 (m, 1H), 2.26-2.10 (m, 2H), 1.97-1.78 (m, 2H). mGluR5 PAMEC₅₀: +++++. Fold shift at 10 μM: ++.

Example 6.19 Synthesis of the HCl salt of8-amino-3-((3-fluorophenyl)ethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

A solution of3-((3-fluorophenyl)ethynyl)-6,7,9,10-tetrahydroazepino[2,1-b]-quinazoline-8,12-dione(0.2 g, 0.58 mmol, 1 equiv) and NaCNBH₃ (3.6 mg, 0.058 mmol, 0.1 equiv)in methanol (15 mL) was heated at reflux overnight. After it was cooledto rt, the reaction mixture was quenched with water and extracted withethyl acetate (3×20 mL). The combined organic layers were dried overNa₂SO₄ and concentrated under reduced pressure to give the desiredproduct, which was purified by silica gel chromatography. The productwas then converted to the corresponding HCl salt. MS (ESI): 348 (M+H⁺);¹H NMR (300 MHz, CD₃OD) δ 8.36-8.33 (d, J=8.52 Hz, 1H), 7.87-7.82 (m,2H), 7.52-7.44 (m, 2H), 7.41-7.36 (m, 1H), 7.28-7.24 (m, 1H), 5.36-5.29(m, 1H), 3.97-3.85 (m, 1H), 3.77-3.69 (m, 1H), 3.58-3.48 (m, 1H),3.44-3.36 (m, 1H), 2.55-2.45 (m, 2H), 2.05-1.92 (m, 1H), 1.87-1.75 (m,1H).

Example 6.20 Synthesis of the HCl salt of3-((3-fluorophenyl)ethynyl)-8-(methylamino)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Example 6.20a Synthesis of tert-butyl3-((3-fluorophenyl)ethynyl)-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-8-ylcarbamate

A solution of8-amino-3((3-fluorophenyl)ethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(0.2 g, 0.58 mmol, 1 equiv), aq. Na₂CO₃ (1 mL) and (Boc)₂O (250.1 mg,1.16 mmol, 2 equiv) in ethyl acetate (15 mL) was stirred at rtovernight. Then the reaction mixture was quenched with water andextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure to give thedesired product, which was purified by silica gel chromatography. MS(ESI): 448 (MH⁺).

Example 6.20b Synthesis of tert-butyl3-((3-fluorophenyl)ethynyl)-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-8-yl(methyl)carbamate

To a stirred mixture oftert-butyl-3-((3-fluorophenyl)ethynyl)-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-8-ylcarbamate(0.3 g, 0.67 mmol, 1 equiv) and NaH (64.3 mg, 2.68 mmol, 4 equiv) in DMF(15 mL) was added CH₃I dropwise. After stirring at rt for 2 hours, thereaction mixture was quenched with water and extracted with ethylacetate (3×20 mL). The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure to give the desired product,which was purified by silica gel chromatography. MS (ESI): 462 (MH⁺).

Example 6.20c Synthesis of the HCl salt of3-((3-fluorophenyl)ethynyl)-8-(methylamino)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

A solution oftert-butyl-3-((3-fluorophenyl)ethynyl)-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-8-yl(methyl)carbamate(0.2 g, 0.43 mmol, 1 equiv) and TFA (2 mL) in DCM (10 mL) was stirred atrt for 2 hours. The reaction mixture was quenched with water andextracted with DCM (3×20 mL). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure to give the desiredproduct, which was purified by silica gel chromatography. MS (ESI): 362(MH⁺). The product was then converted to the corresponding HCl salt. MS(ESI): 362 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.37-8.34 (d, J=8.19 Hz,1H), 7.89-7.86 (m, 2H), 7.52-7.44 (m, 2H), 7.41-7.37 (m, 1H), 7.28-7.21(m, 1H), 5.39-5.32 (m, 1H), 3.94-3.86 (m, 1H), 3.71-3.64 (m, 1H),3.59-3.40 (m, 2H), 2.79 (s, 3H), 2.61-2.55 (m, 2H), 2.11-2.04 (m, 1H),1.93-1.81 (m, 1H).

Example 6.21 Synthesis of the HCl salt of8-(dimethylamino)-3-((3-fluorophenyl)ethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.21d. The product was then converted to thecorresponding HCl salt. MS (ESI): 376 (M+H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.36-8.34 (d, J=8.16 Hz, 1H), 7.88-7.85 (m, 2H), 7.52-7.43 (m, 2H),7.40-7.34 (m, 1H), 7.28-7.19 (m, 1H), 5.44-5.39 (m, 1H), 3.86-3.74 (m,2H), 3.57-3.43 (m, 2H), 2.90 (s, 6H), 2.63-2.53 (m, 2H), 2.24-2.14 (m,1H), 2.03-1.95 (m, 1H).

Example 6.22 Synthesis of3-((3-fluorophenyl)ethynyl)-8-methylene-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

A solution of3-((3-fluorophenyl)ethynyl)-6,7,9,10-tetrahydroazepino[2,1-b]-quinazoline-8,12-dione(0.1 g, 0.29 mmol, 1 equiv) and Tebbe Reagent in THF (5 mL) was stirredat rt for half an hour. Then the reaction mixture was quenched with NaOHaqueous and extracted with ethyl acetate (3×20 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure togive the desired product, which was purified by silica gelchromatography. MS (ESI): 345 (M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ8.26-8.23 (d, J=8.19 Hz, 1H), 7.78 (s, 1H) 7.58-7.55 (dd, J=8.24, 1.52Hz, 1H), 7.38-7.32 (m, 2H), 7.28-7.26 (m, 1H), 7.13-7.06 (m, 1H),4.88-4.86 (d, J=7.50 Hz, 2H), 4.42-4.39 (m, 2H), 3.14-3.10 (m, 2H),2.61-2.51 (m, 4H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 6.23 Synthesis of3-((3-fluorophenyl)ethynyl)-8-(hydroxyimino)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

3-((3-fluorophenyl)ethynyl)-6,7,9,10-tetrahydroazepino[2,1-b]quinazoline-8,12-dione(0.1, 0.29 mmol, 1 equiv) was combined with hydroxylamine hydrochloride(40 mg, 0.58 mmol, 2 equiv) and aqueous Na₂CO₃ (0.5 mL) in a mixture ofMeOH (10 mL) and water (1 mL). The mixture was stirred overnight. Thenthe reaction mixture was diluted with water and extracted with ethylacetate (3×20 mL). The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure to give the desired product,which was purified by silica gel chromatography. MS (ESI): 362 (MH⁺); ¹HNMR (300 MHz, DMSO-d⁶) δ 8.15-8.13 (d, J=7.80 Hz, 1H), 7.76 (s, 1H)7.64-7.59 (d, J=8.10 Hz, 1H), 7.52-7.48 (m, 3H), 7.36-7.33 (m, 1H),4.46-4.35 (m, 2H), 3.15-3.08 (m, 2H), 2.84-2.73 (m, 2H), 2.59-2.55 (m,2H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.

Example 6.24 Synthesis of3-((3-fluorophenyl)ethynyl)-8-(methoxymethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Example 6.24a Synthesis of(Z)-3((3-fluorophenyl)ethynyl)-8-(methoxymethylene)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

To a solution of (methoxymethyl)triphenylphosphonium chloride (171 mg,0.5 mmol, 1 equiv) in 5 mL THF at −78° C. was added n-BuLi (0.2 mL, 0.5mmol, 1 equiv) dropwise and stirred at the same temperature for half anhour. A solution of3-((3-fluorophenyl)ethynyl)-6,7,9,10-tetrahydroazepino[2,1-b]quinazoline-8,12-dione(173 mg, 0.5 mmol, 1 equiv) in THF was then added to the mixturedropwise at the same temperature and stirred for 2 hours. Then thereaction mixture was quenched with water and extracted with ethylacetate (3×20 mL). The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure to give the desired product,which was purified by silica gel chromatography. MS (ESI): 375 (MH⁺).

Example 6.24b Synthesis of3-((3-fluorophenyl)ethynyl)-12-oxo-6,7,8,9,10,11,12-hexahydropazepino[2,1-b]quinazoline-8-carbaldehyde

A solution of(Z)-3-((3-fluorophenyl)ethynyl)-8-(methoxymethylene)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(0.1 g, 0.8 mmol, 1 equiv) and 4N HCl (4 mL) in THF (20 mL) was heatedat reflux for 4 h. After it was cooled to rt, the reaction mixture wasquenched with Na₂CO₃ aqueous and extracted with ethyl acetate (3×50 mL).The combined organic layers were dried over Na₂SO₄. After filtration andconcentration, the residue was purified by silica gel chromatography togive the desired product. MS (ESI): 361 (MH⁺).

Example 6.24c Synthesis of3-((3-fluorophenyl)ethynyl)-8-(hydroxymethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.23. MS (ESI): 363 (MH⁺).

Example 6.24d Synthesis of3-((3-fluorophenyl)ethynyl)-8-(methoxymethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.25. MS (ESI): 377 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.17-8.14 (d, J=8.67 Hz, 1H), 7.75 (s, 1H), 7.64-7.61 (d,J=8.52 Hz, 1H), 7.56-7.53 (d, J=8.5 Hz, 1H), 7.36-7.32 (m, 1H),7.27-7.26 (m, 1H), 7.13-7.07 (m, 1H), 5.29-5.22 (m, 1H), 3.64-3.55 (m,1H), 3.35 (s, 3H), 3.27-3.00 (m, 4H), 2.26-2.21 (m, 4H), 1.52-1.43 (m,1H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: ++.

Example 6.25 Synthesis of the HCl salt of8-((dimethylamino)methyl)-3-((3-fluorophenyl)ethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.21d. The product was then converted to thecorresponding HCl salt. MS (ESI): 390 (M+H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.37-8.35 (d, J=8.73 Hz, 1H), 7.90-7.87 (m, 2H), 7.50-7.44 (m, 2H),7.41-7.40 (m, 1H), 7.28-7.22 (m, 1H), 5.31-5.24 (m, 1H), 4.01-3.92 (m,1H), 3.60-3.54 (m, 1H), 3.14-3.12 (d, J=6.87 Hz, 2H), 2.79 (s, 6H),2.52-2.51 (m, 1H), 2.35-2.23 (m, 2H), 1.73-7.69 (m, 1H), 1.54-1.50 (m,1H), 1.22-1.17 (m, 1H).

Example 6.26 Synthesis of3-((3-fluorophenyl)ethynyl)-4′,5′,9,10-tetrahydro-3′H,6H-spiro[azepino[2,1-b]quinazoline-8,2′-furan]-12(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.11a, Example 4.11b, Example 2.2a, and Example1.1. MS (ESI): 389 (M+H⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ 8.25-8.22 (dd,J=8.27, 0.44 Hz, 1H), 7.76 (s, 1H), 7.56-7.53 (dd, J=8.24, 1.51 Hz, 1H),7.40-7.36 (m, 2H), 7.31-7.28 (m, 1H), 7.13-7.06 (m, 1H), 5.04-4.99 (m,1H), 4.02-3.90 (m, 3H), 3.53-3.43 (m, 1H), 2.95-2.88 (m, 1H), 2.12-1.96(m, 4H), 1.86-1.64 (m, 4H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM:++.

Example 6.27 Synthesis of the HCl salt of3-(pyridin-2-ylethynyl)-4′,5′,9,10-tetrahydro-3′H,6H-spiro[azepino[2,1-b]quinazoline-8,2′-furan]-12(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a. The product was then converted to thecorresponding HCl salt. MS (ESI): 372 (M+H⁺); ¹H NMR (300 MHz, DMSO-d⁶)δ 8.706-8.691 (d, J=4.50 Hz, 1H), 8.240-8.213 (d, J=8.25 Hz, 1H),8.022-7.975 (m, 2H), 7.853-7.793 (m, 2H), 7.579-7.539 (m, 1H), 4.687 (s,1H), 4.020-3.991 (m, 1H), 3.825-3.781 (m, 2H), 3.465-3.384 (m, 1H),3.184-3.135 (m, 1H), 2.005-1.656 (m, 8H). mGluR5 PAM EC₅₀: +++. Foldshift at 10 μM: +++.

Example 6.28 Synthesis of3-((3-fluorophenyl)ethynyl)-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-pyrrolidine]-5′,12(7H)-dione

Example 6.28a Synthesis of tert-butyl2,8-dioxo-1-azaspiro[4.5]decane-1-carboxylate

A solution of 1-azaspiro[4.5]decane-2,8-dione (0.9 g, 5.4 mmol, 1equiv), Et₃N (545 mg, 5.4 mmol, 1 equiv), DMAP (132 mg, 1.08 mmol, 0.2equiv) and di-tert-butyl dicarbonate (2.3 g, 10.8 mmol, 2 equiv) in THF(50 mL) was stirred at rt for 3 hours. The reaction mixture was dilutedwith aqueous Na₂CO₃ and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were dried over Na₂SO₄. After filtration andconcentration, the residue was used for the next step.

Example 6.28b Synthesis of tert-butyl8-(hydroxyimino)-2-oxo-1-azaspiro[4.5]decane-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 4.11a.

Example 6.28c Synthesis of tert-butyl2,9-dioxo-1,8-diazaspiro[4.6]undecane-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 4.11b.

Example 6.28d Synthesis of tert-butyl3-bromo-5′,12-dioxo-7,9,10,12-tetrahydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-pyrrolidine]-1′-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 2.2a.

Example 6.28e Synthesis of3-bromo-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-pyrrolidine]-5′,12(7H)-dione

The title compound was prepared according to the experimental procedureas described in Example 1.21c.

Example 6.28f Synthesis of3-bromo-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-pyrrolidine]-5′,12(7H)-dione

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 402 (M+H⁺); ¹H NMR (300 MHz,DMSO-d⁶) δ 8.29-8.28 (m, 1H), 8.14-8.12 (d, J=7.75 Hz, 1H), 7.75 (s,1H), 7.64-7.60 (m, 1H), 7.55-7.46 (m, 3H), 7.36-7.31 (m, 1H), 4.50-4.19(m, 2H), 3.18-3.17 (m, 1H), 3.10-3.00 (m, 1H), 2.28-2.23 (m, 2H),1.99-1.77 (m, 6H).

Example 6.29 Synthesis of the HCl salt of3-((3-fluorophenyl)ethynyl)-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-pyrrolidin]-12(7H)-one

Example 6.29a Synthesis of 1,4-dioxa-9-azadispiro[4.2.4⁸.2⁵]tetradecane

To a solution of 1,4-dioxa-9-azadispiro[4.2.4⁸0.2⁵]tetradecan-10-one(1.5 g, 7.1 mmol, 1 equiv) in dry THF (100 mL) was added LiAlH₄ (3 g,78.9 mmol, 11 equiv) in portions and heated at reflux overnight. Afterit was cooled to rt, the reaction mixture was quenched with 1 N NaOH andextracted with DCM (3×100 mL). The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure to give the desiredproduct for the next step.

Example 6.29b Synthesis of9H-fluoren-9-ylmethyl-1,4-dioxa-9-azadispiro[4.2.4⁸0.2⁵]tetradecane-9-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 5.1a.

Example 6.29c Synthesis of (9H-fluoren-9-yl)methyl8-oxo-1-azaspiro[4.5]decane-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 6.14b.

Example 6.29d Synthesis of (9H-fluoren-9-yl)methyl8-(hydroxyimino)-1-azaspiro[4.5]decane-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 4.11a.

Example 6.29e Synthesis of (9H-fluoren-9-yl)methyl9-oxo-1,8-diazaspiro[4.6]undecane-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 4.11b.

Example 6.29f Synthesis of (9H-fluoren-9-yl)methyl3-bromo-12-oxo-7,9,10,12-tetrahydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-pyrrolidine]-1′-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 2.2a.

Example 6.29g Synthesis of3-bromo-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-pyrrolidin]-12(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 3.17b.

Example 6.29h Synthesis of the HCl salt of3-((3-fluorophenyl)ethynyl)-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-pyrrolidin]-12(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 388 (M+H⁺); ¹H NMR (300 MHz, CD₃OD) δ8.35-8.32 (d, J=9.00 Hz, 1H), 7.86-7.82 (m, 2H), 7.49-7.48 (m, 2H),7.39-7.36 (m, 1H), 7.27-7.21 (m, 1H), 4.91-4.90 (m, 1H), 4.15-4.08 (m,1H), 3.50-3.31 (m, 4H), 2.40-2.10 (m, 8H).

Example 6.30 Synthesis of the HCl salt of((3-fluorophenyl)ethynyl)-1′-methyl-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-pyrrolidin]-12(7H)-one

To a solution of3-((3-fluorophenyl)ethynyl)-9,10-dihydro-6H-spiro[azepino[2,1-b]-quinazoline-8,2′-pyrrolidin]-12(7H)-one(80 mg, 0.21 mmol, 1 eq) and K₂CO₃ (116 mg, 0.82 mmol, 4 eq) in acetone(20 mL) was added dimethyl sulfite (25.4 mg, 0.23 mmol, 1.1 equiv).After stirring at rt for 1 h, the mixture was quenched with water andextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure to give thedesired product, which was purified by silica gel chromatography. Theproduct was then converted to the corresponding HCl salt. MS (ESI): 402(M+H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.32-8.29 (d, J=8.31 Hz, 1H),7.83-7.76 (m, 2H), 7.51-7.42 (m, 2H), 7.38-7.33 (m, 1H), 7.26-7.19 (m,1H), 5.42-5.31 (m, 1H), 3.84-3.63 (m, 5H), 2.80 (s, 3H), 2.70-2.65 (m,1H), 2.40-2.09 (m, 7H).

Example 6.31 and Example 6.32 Synthesis of3-((3-fluorophenyl)ethynyl)-6-isobutyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand3-((4-fluorophenyl)ethynyl)-10-isobutyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compounds were prepared according to the experimentalprocedure as described in Example 4.11b, Example 2.2a, and Example 1.1.

3-((3-fluorophenyl)ethynyl)-6-isobutyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

MS (ESI): 389 (M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.21 (dd, J=8.25,0.48 Hz, 1H), 7.82 (s, 1H), 7.62-7.52 (m, 3H), 7.13-7.05 (m, 2H),5.19-5.14 (m, 1H), 3.79-3.68 (m, 1H), 3.14-3.06 (m, 1H), 2.18-2.11 (m,1H), 2.06-1.80 (m, 4H), 1.80-1.70 (m, 2H), 1.50-1.44 (m, 2H), 1.02-0.98(m, 6H).

3-((4-fluorophenyl)ethynyl)-10-isobutyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

MS (ESI): 389 (MH⁺). mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM: +.

Example 6.33 Synthesis of10-allyl-3-((4-fluorophenyl)ethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.11a, Example 4.11b, Example 2.2a, and Example1.1. MS (ESI): 373 (M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.23-8.20 (d,J=8.25 Hz, 1H), 7.72 (s, 1H), 7.59-7.52 (m, 3H), 7.12-7.05 (t, J=8.69Hz, 2H), 5.92-5.74 (m, 2H), 5.15-5.03 (m, 2H), 3.18-3.14 (m, 2H),2.74-2.69 (t, J=7.52 Hz, 2H), 2.21-2.07 (m, 2H), 1.94-1.74 (m, 3H),1.71-1.62 (m, 1H). mGluR5 PAM EC₅₀: ++++.

Example 6.34 Synthesis of3-((3-fluorophenyl)ethynyl)-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]dioxolan]-12(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 391 (M+H⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.26-8.23 (d, J=8.25 Hz, 1H), 7.77 (s, 1H), 7.58-7.55 (dd,J=8.21, 1.52 Hz, 1H), 7.38-7.34 (m, 2H), 7.30-7.29 (m, 1H), 7.14-7.07(m, 1H), 4.47-4.46 (m, 2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H), 2.06-2.03(m, 2H), 1.99-1.96 (m, 2H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM:+++.

Example 6.35 Synthesis of6-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Example 6.35a Synthesis of 3-methylazepan-2-one

To a solution of azepan-2-one (0.5 g, 4.42 mmol, 1 equiv) in anhydrousTHF (20 mL) under nitrogen, was added n-BuLi (4.4 mL, 2.5 M in n-hexane,11.06 mmol) dropwise at 0° C. The reaction mixture was kept at 0° C. for2 h, then MeI (0.3 mL, 4.86 mmol) was added. After stirring for 1 h, themixture was quenched with water and extracted with DCM (2×50 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration and concentration, the crude product was directly used forthe next step without further purification. MS (ESI): 128 (MH⁺).

Example 6.35b Synthesis of3-bromo-6-methyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a. MS (ESI): 307, 309 (MH⁺).

Example 6.35c Synthesis of6-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 330 (MH⁺); ¹H NMR (300 MHz,CD₃OD) δ 8.92-8.90 (d, J=5.67 Hz, 1H), 8.64-8.58 (m, 1H), 8.41-8.38 (d,J=8.28 Hz, 1H), 8.31-8.28 (d, J=8.10 Hz, 1H), 8.24 (s, 1H), 8.09-8.05(m, 1H), 7.95-7.92 (dd, J=8.28, 1.26 Hz, 1H), 5.00-4.99 (m, 1H),4.19-4.12 (m, 1H), 3.69-3.64 (m, 1H), 2.03-1.92 (m, 4H), 1.83-1.65 (m,2H), 1.61-1.59 (d, J=6.90 Hz, 3H). mGluR5 PAM EC₅₀: ++++. Fold shift at10 μM: ++.

Example 6.36 and Example 6.42 Synthesis of7-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand9-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compounds were prepared according to the experimentalprocedure as described in Example 4.11a, Example 4.11b, Example 2.2a,and Example 1.1.

7-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

MS (ESI): 330 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.88-8.86 (d, J=5.01 Hz,1H), 8.53-8.47 (t, J=7.94 Hz, 1H), 8.44-8.42 (d, J=8.31 Hz, 1H),8.22-8.20 (d, J=8.04 Hz, 1H), 8.05 (s, 1H), 8.01-7.95 (m, 2H), 5.10-5.03(m, 1H), 4.07-3.99 (m, 1H), 3.42-3.31 (m, 1H), 3.20-3.15 (d, J=14.44 Hz,1H), 2.13-2.04 (m, 3H), 1.75-1.69 (m, 2H), 1.23-1.21 (d, J=6.75 Hz, 3H).mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: ++.

9-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

MS (ESI): 330 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.92-8.90 (d, J=5.3 Hz,1H), 8.61-8.55 (t, 7.92 Hz, 1H), 8.46-8.43 (d, J=8.25 Hz, 1H), 8.29-8.26(d, J=8.01 Hz, 1H), 8.09-8.00 (m, 3H), 4.91-4.84 (d, J=14.29 Hz, 1H),4.04-3.96 (m, 1H), 3.54-3.31 (m, 2H), 2.21 (m, 1H), 2.09-1.92 (m, 3H),1.71-1.65 (m, 1H), 1.13-1.11 (d, J=6.90 Hz, 3H). mGluR5 PAM EC₅₀: +++++.Fold shift at 10 μM: +++.

Example 6.36a and Example 6.36b Separation of7-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneinto(S)-7-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-7-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Racemic7-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-onewas separated into the corresponding two single enantiomer compounds(S)-7-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-7-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 4.6×100 mm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was methanol:isopropanol (3:1) with 0.1%isopropylamine. Isocratic Method: 45% Co-solvent at 4 mL/min SystemPressure: 100 bar. Column Temperature 25° C.

Faster moving enantiomer of7-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 1): Retention time=2.4 min 99% ee.Slower moving enantiomer of7-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 2): Retention time=## min. ##% ee.

Example 6.42a and Example 6.42b Separation of9-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(S)-9-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-9-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Racemic9-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-onewas separated into the corresponding two single enantiomer compounds(S)-9-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-9-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 4.6×100 mm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was methanol:isopropanol (2:1) with 0.1%isopropylamine. System Pressure: 100 bar. Column Temperature 25° C.

Faster moving enantiomer of9-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 1): Retention time=3.0 minSlower moving enantiomer of9-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 2): Retention time=3.9 min

Example 6.37 and Example 6.43 Synthesis of7,7-dimethyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand Synthesis of9,9-dimethyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compounds were prepared according to the experimentalprocedures as described in Example 4.11a, Example 4.11b, Example 2.2a,and Example 1.1. The title compounds were separated after the last step.

7,7-dimethyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

MS (ESI): 344 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.98-8.96 (d, J=5.37 Hz,1H), 8.75-8.69 (t, J=7.98 Hz, 1H), 8.47-8.45 (d, J=8.16 Hz, 1H),8.41-8.38 (d, J=8.16 Hz, 1H), 8.23 (s, 1H), 8.20-8.14 (m, 1H), 8.08-8.05(dd, J=8.28, 1.23 Hz, 1H), 4.85-4.32 (m, 2H), 3.39 (s, 2H), 2.00-1.90(m, 2H), 1.86-1.82 (m, 2H), 1.18 (s, 6H). mGluR5 PAM EC₅₀: +++++.

9,9-dimethyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one:MS (ESI): 344 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.91 (s,H), 8.58-8.53 (t,J=7.46 Hz, 1H), 8.44-8.41 (d, J=8.28 Hz, 1H), 8.28-8.25 (d, J=8.01 Hz,1H), 8.11 (s, 1H), 8.05-7.99 (m, 2H), 4.65-4.01 (broad s, 2H), 3.32 (s,2H), 2.05 (broad s, 2H), 1.78-1.74 (t, J=11.77 Hz, 2H), 1.19-1.05 (s,6H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: +++.

Example 6.38 Synthesis of3-(pyridin-2-ylethynyl)-8-(trifluoromethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.11a, Example 4.11b, Example 2.2a and Example1.1. MS (ESI): 384 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.93-8.91 (d, J=5.04Hz, 1H), 8.64-8.58 (t, J=6.6 Hz, 1H), 8.46-8.43 (d, J=8.31 Hz, 1H),8.32-8.29 (d, J=8.04 Hz, 1H), 8.10-7.99 (m, 3H), 5.40-5.32 (dd, J=15.0,5.0 Hz, 1H), 3.95-3.87 (dd, J=15.0, 11.1 Hz, 1H), 3.54-3.31 (m, 2H),2.94-2.83 (m, 1H), 2.42-2.41 (m, 2H), 1.99-1.86 (m, 1H), 1.81-1.69 (m,1H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++.

Example 6.38a and Example 6.38b Separation of3-(pyridin-2-ylethynyl)-8-(trifluoromethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneinto(S)-3-(pyridin-2-ylethynyl)-8-(trifluoromethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-3-(pyridin-2-ylethynyl)-8-(trifluoromethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Racemic3-(pyridin-2-ylethynyl)-8-(trifluoromethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-onewas separated into the corresponding two single enantiomer compounds(S)-3-(pyridin-2-ylethynyl)-8-(trifluoromethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-(pyridin-2-ylethynyl)-8-(trifluoromethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 4.6×100 mm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was methanol:isopropanol (1:3) with 0.1%isopropylamine. Isocratic Method: 40% Co-solvent at 4 mL/min. SystemPressure: 100 bar. Column Temperature 25° C.

Faster moving enantiomer of3-(pyridin-2-ylethynyl)-8-(trifluoromethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 1): Retention time=1.4 min 100% ee.Slower moving enantiomer of3-(pyridin-2-ylethynyl)-8-(trifluoromethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 2): Retention time=2.5 min 99.1% ee.

Example 6.39 Synthesis of the HCl salt of12-oxo-3-(pyridin-2-ylethynyl)-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline-8-carbonitrile

Example 6.39a Synthesis of3-bromo-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-8-ylmethanesulfonate

To a stirred solution of3-bromo-8-hydroxy-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(290 mg, 0.938 mmol) and excess Et₃N in DCM (10 mL) was added Ms-Cl(0.76 mL). The mixture was stirred for 1.5 h at room temperature. Thenthe reaction mixture was diluted with water and extracted with EtOAc(3×50 mL). The combined organic layers were dried over Na₂SO₄. Afterfiltration and concentration, the crude product was directly used forthe next step. MS (ESI): 387, 389 (MH⁺).

Example 6.39b Synthesis of3-bromo-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline-8-carbonitrile

A solution of2-bromo-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-8-ylmethanesulfonate (0.3 g) and NaCN (0.5 g, 10.2 mmol, 13 equiv) in DMSO(20 mL) was stirred at 90° C. overnight. After it was cooled to rt, thereaction mixture was diluted with water and extracted with ethyl acetate(3×100 mL). The combined organic layers were dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by silica gelchromatography to give 36 mg of the desired product.

Example 6.39c Synthesis of the HCl salt of12-oxo-3-(pyridin-2-ylethynyl)-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline-8-carbonitrile

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 341 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ8.68-8.67 (d, J=4.83 Hz, 1H), 8.26-8.23 (d, J=8.25 Hz, 1H), 7.84 (s,1H), 7.77-7.75 (t, J=7.8 Hz, 1H), 7.67-7.64 (d, J=8.22 Hz, 1H),7.61-7.58 (d, J=7.8 Hz, 1H), 7.34-7.28 (m, 1H), 4.71 (br s, 1H), 4.37(br s, 1H), 3.41-3.33 (m, 1H), 3.19-3.09 (m, 2H), 2.30-2.20 (m, 3H),2.17-2.07 (m, 1H). mGluR5 PAM EC₅₀: ++.

Example 6.40 Synthesis of8,8-dimethyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.11a, Example 4.11b, Example 2.2a and Example1.1. MS (ESI): 344 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.97-8.95 (d, J=5.79Hz, 1H), 8.70-8.66 (t, J=7.99 Hz, 1H), 8.47-8.44 (d, J=8.28 Hz, 1H),8.39-8.36 (d, J=8.01 Hz, 1H), 8.15-8.11 (m, 2H), 8.06-8.03 (dd, J=8.30,1.31 Hz, 1H), 4.52 (broad, 2H), 3.39-3.31 (m, 2H), 1.89-1.86 (d, J=11.4Hz, 2H), 1.73-1.70 (t, J=5.1 Hz, 2H), 1.14 (s, 6H). mGluR5 PAM EC₅₀:+++++. Fold shift at 10 μM: +++.

Example 6.41 Synthesis of8,8-difluoro-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.41. MS (ESI): 352 (MH⁺); ¹H NMR (300 MHz,CD₃OD) δ 8.93-8.91 (d, J=5.70 Hz, 1H), 8.65-8.59 (t, J=7.91 Hz, 1H),8.44-8.41 (d, J=8.25 Hz, 1H), 8.32-8.29 (d, J=8.01 Hz, 1H), 8.29-8.10(m, 2H), 8.07-7.96 (d, J=8.31 Hz, 1H), 4.59-4.58 (m, 2H), 3.41-3.36 (m,2H), 2.56-2.38 (m, 4H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: +++.

Example 6.44 Synthesis of10-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 330 (MH⁺); ¹HNMR (300 MHz, CD₃OD) δ 8.86-8.85 (d, J=5.34 Hz, 1H), 8.49-8.42 (m, 2H),8.19-8.17 (d, J=7.80 Hz, 1H), 8.03-7.92 (m, 3H), 5.93-5.91 (m, 1H),3.60-3.49 (m, 2H), 2.25-2.18 (m, 1H), 2.13-2.08 (m, 2H), 2.00-1.84 (m,3H), 1.63-1.61 (d, J=7.35 Hz, 3H). mGluR5 PAM EC₅₀: +++++. Fold shift at10 μM: ++.

Example 6.44a and Example 6.44b Separation of10-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneinto(S)-10-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-10-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Racemic10-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-onewas separated into the corresponding two single enantiomer compounds(S)-10-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-10-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 4.6×100 mm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was methanol:isopropanol (2:1) with 0.1%isopropylamine. Isocratic Method: 55% Co-solvent at 4 mL/min SystemPressure: 100 bar. Column Temperature 25° C.

Faster moving enantiomer of10-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 1): Retention time=1.3 min 99.3% ee.Slower moving enantiomer of10-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 2): Retention time=1.9 min 99.4% ee.

Example 6.45 Synthesis of the HCl salt of6-((12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-3-yl)ethenyl)picolinonitrile

The title compound was prepared according to the experimental procedureas described in Example 5.1d, Example 5.1e, and Example 1.1. The productwas then converted to the corresponding HCl salt. MS (ESI): 341 (MH⁺);¹H NMR (300 MHz, CD₃OD) δ 8.40-8.37 (d, J=8.2 Hz, 1H), 8.14-8.09 (t,J=7.8 Hz, 1H), 7.99-7.92 (m, 4H), 4.57-4.54 (m, 2H), 3.55-3.40 (m, 2H),2.04-1.89 (m, 6H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: +++.

Example 6.46 Synthesis of8-fluoro-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Example 6.46a Synthesis of3-bromo-8-fluoro-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

To a stirred solution of3-bromo-8-hydroxy-7,8,9,10-tetrahydroazepino[2,1-b]-quinazolin-12(6H)-one(200 mg, 0.64 mmol, 1 equiv) in DCM was added excess DAST under N₂ at−78° C. After that, the resulting mixture was stirred at −78° C. for 3h. The reaction mixture was quenched with water (20 mL) and extractedwith ethyl acetate (3×20 mL). The combined organic extract was driedover Na₂SO₄. After filtration and concentration, the crude product waspurified by silica gel chromatography to give 200 mg of the desiredproduct. MS (ESI): 311, 313 (MH⁺).

Example 6.46b Synthesis of the HCl salt of8-fluoro-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 334 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.89-8.88 (d, J=5.25 Hz, 1H), 8.54-8.51 (t, J=8.10 Hz, 1H), 8.44-8.42(d, J=8.25 Hz, 1H), 8.25-8.22 (d, J=7.98 Hz, 1H), 8.03-7.97 (m, 3H),4.91-4.85 (m, 1H), 4.47-4.34 (t, J=18.60 Hz, 1H), 3.77-3.64 (t, J=18.70Hz, 1H), 3.19-3.17 (m, 1H), 2.54-2.22 (m, 3H), 2.21-1.95 (m, 2H). mGluR5PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 6.47 Synthesis of the HCl salt of6-((8-methyl-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-3-yl)ethynyl)picolinonitrile

The title compound was prepared according to the experimental procedureas described in Example 5.1d, Example 5.1e, and Example 1.1. The productwas then converted to the corresponding HCl salt. MS (ESI): 355 (MH⁺);¹H NMR (300 MHz, CD₃OD) δ 8.40-8.37 (d, J=8.1 Hz, 1H), 8.14-8.09 (t,J=7.8 Hz, 1H), 7.99-7.92 (m, 4H), 5.20-5.18 (m, 1H), 3.93-3.88 (m, 1H),3.45-3.40 (m, 1H), 3.26-3.23 (m, 1H), 2.16-2.09 (m, 3H), 1.64-1.56 (m,1H), 1.40-1.30 (m, 1H), 1.07-1.04 (d, J=6.5 Hz, 3H). mGluR5 PAM EC₅₀:+++. Fold shift at 10 μM: +++.

Example 6.48 Synthesis of the HCl salt of8-fluoro-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.45, Example 6.46, and Example 1.1. The productwas then converted to the corresponding HCl salt. MS (ESI): 348 (MH⁺);¹H NMR (300 MHz, DMSO-d⁶) δ 8.68-8.67 (d, J=4.23 Hz, 1H), 8.20-8.18 (d,J=8.22 Hz, 1H), 7.99-7.93 (td, J=7.80, 1.80 Hz, 1H), 7.90 (s, 1H),7.81-7.78 (d, J=7.80 Hz, 1H), 7.74-7.71 (dd, J=8.22, 1.38 Hz, 1H),7.55-7.50 (t, J=6.00 Hz, 1H), 4.84-4.77 (dd, J=14.70, 5.10 Hz, 1H),3.99-3.90 (dd, J=12.00, 14.70 Hz, 1H), 3.43-3.39 (d, J=13.20 Hz, 1H),2.97-2.90 (dd, J=6.30, 14.40 Hz, 1H), 2.21-2.16 (m, 2H), 1.97-1.75 (m,2H), 1.39-1.32 (d, J=21.60 Hz, 3H). mGluR5 PAM EC₅₀: +++++. Fold shiftat 10 μM: +++.

Example 6.48a and Example 6.48b Separation of8-fluoro-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneinto(S)-8-fluoro-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-8-fluoro-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Racemic8-fluoro-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-onewas separated into the corresponding two single enantiomer compounds(S)-8-fluoro-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-8-fluoro-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 4.6×100 mm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was methanol:isopropanol (1:3) with 0.1%isopropylamine. Isocratic Method: 50% Co-solvent at 4 mL/min. SystemPressure: 100 bar. Column Temperature 25° C.

Faster moving enantiomer of8-fluoro-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 1): Retention time=1.0 min 96.4% ee. mGluR5 PAM EC₅₀: +++++.Fold shift at 10 μM: +++.Slower moving enantiomer of8-fluoro-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 2): Retention time=2.2 min 96.0% ee. mGluR5 PAM EC₅₀: +++++.Fold shift at 10 μM: ++.

Example 6.49 Synthesis of the HCl salt of8-hydroxy-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 346 (MH+); ¹H NMR (300 MHz, DMSO-d⁶) δ8.68-8.67 (d, J=4.50 Hz, 1H), 8.21-8.18 (d, J=8.25 Hz, 1H), 7.94-7.81(m, 2H), 7.81-7.74 (dd, J=7.80, 12.30 Hz, 2H), 7.54-7.50 (m, 1H),4.74-4.69 (t, J=8.10 Hz, 1H), 4.03-3.94 (t, J=10.80 Hz, 1H), 3.54-3.45(t, J=13.20 Hz, 1H), 2.97-2.89 (dd, J=14.40, 6.95 Hz, 1H), 1.84-1.78 (m,3H), 1.65-1.57 (m, 1H), 1.15 (s, 3H). mGluR5 PAM EC₅₀: ++ Fold shift at10 μM: +++.

Example 6.50 Synthesis of the HCl salt of8-methoxy-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.46, and Example 1.1. The product was thenconverted to the corresponding HCl salt. MS (ESI): 360 (MH⁺). MS (ESI):360 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ 8.69-8.68 (d, J=4.62 Hz, 1H),8.22-8.19 (d, J=8.25 Hz, 1H), 7.99-7.95 (m, 2H), 7.83-7.76 (dd, J=11.40,8.10 Hz, 2H), 7.56-7.52 (m, 1H), 4.78-4.76 (m, 1H), 3.91-3.82 (t,J=11.70 Hz, 1H), 3.41-3.32 (t, J=13.80 Hz, 1H), 3.18 (s, 3H), 3.02-2.94(dd, J=13.50, 6.90 Hz, 1H), 2.16-2.02 (m, 2H), 1.80-1.71 (t, J=13.50 Hz,1H), 1.65-1.56 (t, J=12.90 Hz, 1H), 1.11 (s, 3H). mGluR5 PAM EC₅₀: +++.Fold shift at 10 μM: ++.

Example 6.50a and Example 6.50b Separation of8-methoxy-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneinto(S)-8-methoxy-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-8-methoxy-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

Racemic8-methoxy-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-onewas separated into the corresponding two single enantiomer compounds(S)-8-methoxy-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneand(R)-8-methoxy-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 4.6×100 mm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was methanol:isopropanol (1:1) with 0.1%isopropylamine. Isocratic Method: 45% Co-solvent at 4 mL/min. SystemPressure: 100 bar. Column Temperature 25° C.

Faster moving enantiomer of8-methoxy-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 1): Retention time=2.1 min 96.5% ee. mGluR5 PAM EC₅₀: +++.Fold shift at 10 μM: +++.Slower moving enantiomer of8-methoxy-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(fraction 2): Retention time=2.8 min 98.8% ee. mGluR5 PAM EC₅₀: ++++.Fold shift at 10 μM: ++.

Example 6.51 Synthesis of the HCl salt of3-(pyridin-2-ylethynyl)-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,1′-cyclopropan]-12(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.11a, Example 4.11b, Example 2.2a, and Example1.1. The product was then converted to the corresponding HCl salt. MS(ESI): 342 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.91-8.89 (d, J=5.6 Hz, 1H),8.61-8.53 (t, J=7.8 Hz, 1H), 8.46-8.44 (d, J=8.3 Hz, 1H), 8.28-8.25 (d,J=8.0 Hz, 1H), 8.09 (s, 1H), 8.05-8.00 (m, 2H), 4.75-4.50 (m, 2H),3.47-3.43 (m, 2H), 1.89-1.86 (m, 2H), 1.81-1.63 (m, 2H), 0.58 (s, 4H).mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: +++.

Example 6.52 Synthesis of10-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.11a, Example 4.11b, Example 2.2a and Example1.1. The title compound was separated from6-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one.Data for the title compound: MS (ESI): 330 (MH⁺); ¹H NMR (300 MHz,CD₃OD) δ 8.86-8.85 (d, J=5.34 Hz, 1H), 8.49-8.42 (m, 2H), 8.19-8.17 (d,J=7.80 Hz, 1H), 8.03-7.92 (m, 3H), 5.93-5.91 (m, 1H), 3.60-3.49 (m, 2H),2.25-2.18 (m, 1H), 2.13-2.08 (m, 2H), 2.00-1.84 (m, 3H), 1.63-1.61 (d,J=7.35 Hz, 3H).

Example 6.53 Synthesis of1-fluoro-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental proceduresdescribed in Example 4.27b and Example 1.1. MS (ESI): 348 (MH⁺).

Example 6.54 Synthesis of1-chloro-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental proceduresdescribed in Example 4.27b and Example 1.1. MS (ESI): 348 (MH⁺).

Example 7.1 through Example 7.69 Method A

A solution of3-bromo-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]-dioxolan]-12(7H)-one(0.1 g, 0.28 mmol, 1 equiv), the required ethyne (0.56 mmol, 2 equiv),Pd(OAc)₂ (6.3 mg, 0.028 mmol, 0.1 equiv), PPh₃ (66 mg, 0.252 mmol, 0.9equiv), CuI (5.3 mg, 0.028 mmol, 0.1 equiv) and Et₃N (0.5 mL) in DMF (8mL) was stirred in a sealed tube at 70° C. for 3.5 hours. After it wascooled to room temperature, the reaction mixture was diluted with H₂Oand extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine and dried over anhydrous sodium sulfate, thenconcentrated under reduced pressure to give the desired product, whichwas purified by silica gel chromatography.

Method B

Example 7.1a Synthesis of3-((trimethylsilyl)ethynyl)-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]dioxolan]-12(7H)-one

A solution of3-bromo-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]dioxolan]-12(7H)-one(1.74 g, 4.96 mmol, 1 equiv), ethynyltrimethylsilane (972 mg, 9.92 mmol,2 equiv), Pd(OAc)₂ (223.2 mg, 0.992 mmol, 0.2 equiv), PPh₃ (1.04 g, 3.96mmol, 0.8 equiv), CuI (189 mg, 0.992 mmol, 0.2 equiv) and Et₃N (1.3 mL)in DMF (50 mL) was stirred in a sealed tube at 70° C. for 3.5 hours.After it was cooled to room temperature, the reaction mixture wasdiluted with H₂O and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine and dried over anhydroussodium sulfate, then concentrated under reduced pressure. The productwas obtained by silica gel chromatography purification.

Example 7.1b Synthesis of3-ethynyl-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]dioxolan]-12(7H)-one

A solution of3-((trimethylsilyl)ethynyl)-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]dioxolan]-12(7H)-one(1.5 g, 4.1 mmol, 1 equiv) and 1 N aq. KOH in methanol was stirred at rtfor half an hour. The reaction mixture was quenched with water andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine and dried over anhydrous sodium sulfate, thenconcentrated under reduced pressure. The product was obtained by silicagel chromatography purification.

Example 7.1c Synthesis of substituted3-ethynyl-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]dioxolan]-12(7H)-ones

A solution of3-ethynyl-9,10-dihydro-6H-spiro[azepino[2,1-b]quinazoline-8,2′-[1,3]-dioxolan]-12(7H)-one(0.1 g, 0.34 mmol, 1 equiv), the required R¹—Br (0.68 mmol, 2 equiv),Pd(OAc)₂ (7.6 mg, 0.034 mmol, 0.1 equiv), PPh₃ (80.2 mg, 0.0.31 mmol,0.9 equiv), CuI (6.5 mg, 0.034 mmol, 0.1 equiv) and Et₃N (0.5 mL) in DMF(8 mL) was stirred in a sealed tube at 70° C. for 3.5 hours. After itwas cooled to room temperature, the reaction mixture was diluted withH₂O and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine and dried over anhydrous sodium sulfate,then concentrated under reduced pressure. The product was obtained bysilica gel chromatography purification.

Example Structure/Compound # Method & Data Example 7.1

Method A; MS (ESI): 373 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.22 (d, J= 8.19 Hz, 1H), 7.77 (s, 1H), 7.60-7.56 (m, 3H), 7.40-7.38 (m, 3H),4.47-4.45 (m, 2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H), 2.06-1.96 (m, 4H).mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: +. Example 7.2

Method A; MS (ESI): 391; ¹H NMR (300 MHz, CDCl₃) δ 8.26-8.23 (dd, J =8.28, 0.48 Hz, 1H), 7.81 (s, 1H), 7.61-7.54 (m, 2H), 7.41-7.34 (m, 1H),7.20-7.11 (m, 2H), 4.46-4.45 (m, 2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H),2.06-1.96 (m, 4H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.Example 7.3

Method A; MS (ESI): 391; ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.22 (d, J =8.28 Hz, 1H), 7.75 (s, 1H), 7.59-7.54 (m, 3H), 7.13-7.06 (t, J = 8.72Hz, 2H), 4.46-4.45 (m, 2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H), 2.06-1.95(m, 4H). mGluR5 PAM EC₅₀: +++. Example 7.4

Method A; MS (ESI): 409; ¹H NMR (300 MHz, CDCl₃) δ 8.26-8.23 (d, J =8.16 Hz, 1H), 7.90 (s, 1H), 7.59-7.28 (m, 2H), 6.95-6.88 (m, 2H), 4.46-4.45 (m, 2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H), 2.06-1.96 (m, 4H).Example 7.5

Method B; MS (ESI): 409; ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.23 (d, J =8.24 Hz, 1H), 7.75 (s, 1H), 7.56-7.53 (dd, J = 8.22, 1.53 Hz, 1H), 7.43-7.28 (m, 2H), 7.23-7.14 (m, 1H), 4.51-4.40 (m, 2H), 4.05 (s, 4H),3.17-3.13 (m, 2H), 2.06-1.96 (m, 4H). mGluR5 PAM EC₅₀: ++. Fold shift at10 μM: +++. Example 7.6

Method B; MS (ESI): 405; ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.22 (d, J = 8.3Hz, 1H), 7.77 (s, 1H), 7.57-7.49 (m, 2H), 7.01-6.88 (m, 2H), 4.46 (m,2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H), 2.54 (s, 3H), 2.06-1.96 (m, 4H).mGluR5 PAM EC₅₀: +. Example 7.7

Method A; MS (ESI): 407; ¹H NMR (300 MHz, CDCl₃) δ 8.26-8.24 (d, J =8.58 Hz, 1H), 7.83 (s, 1H), 7.63-7.59 (m, 2H), 7.49-7.46 (m, 1H), 7.35-7.30 (m, 2H), 4.47-4.46 (m, 2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H),2.06-1.96 (m, 4H). Example 7.8

Method A; MS (ESI): 407; ¹H NMR (300 MHz, CDCl₃) δ 8.26-8.23 (d, J =8.31 Hz, 1H), 7.76 (s, 1H), 7.57-7.54 (m, 2H), 7.48-7.45 (m, 1H), 7.39-7.32 (m, 2H), 4.47-4.46 (m, 2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H),2.06-1.96 (m, 4H). mGluR5 PAM EC₅₀: +. Example 7.09

Method A; MS (ESI): 407; ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.22 (d, J =8.28 Hz, 1H), 7.76 (s, 1H), 7.57-7.49 (m, 3H), 7.39-7.35 (m, 2H), 4.47-4.46 (m, 2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H), 2.06-1.96 (m, 4H). mGluR5PAM EC₅₀: +. Example 7.10

Method A; MS (ESI): 374; ¹H NMR (300 MHz, DMSO-d⁶) δ 8.71-8.69 (d, J =4.4 Hz, 1H), 8.24- 8.21 (d, J = 8.3 Hz, 1H), 8.02-7.97 (m, 2H), 7.85-7.77 (m, 2H), 7.58-7.54 (m, 1H), 4.33-4.32 (m, 2H), 3.96 (s, 4H),3.24-3.17 (m, 2H), 2.02-1.93 (m, 4H). mGluR5 PAM EC₅₀: +++. Fold shiftat 10 μM: +++. Example 7.11

Method A; MS (ESI): 374; ¹H NMR (300 MHz, CDCl₃) δ 8.82 (s, 1H),8.61-8.60 (m, 1H), 8.27- 8.24 (d, J = 8.61 Hz, 1H), 7.88-7.85 (m, 1H),7.79 (s, 1H), 7.60-7.56 (dd, J = 8.24, 1.52 Hz, 1H), 7.36-7.31 (m, 1H),4.45-4.44 (m, 2H), 4.05 (s, 4H), 3.17-3.14 (m, 2H), 2.06-1.96 (m, 4H).mGluR5 PAM EC₅₀: +. Example 7.12

Method A; MS (ESI): 374; ¹H NMR (300 MHz, CDCl₃) δ 8.67-8.65 (d, J =6.03 Hz, 2H), 8.28- 8.25 (d, J = 8.25 Hz, 1H), 7.80 (s, 1H), 7.60-7.57(dd, J = 8.25, 1.47 Hz, 1H), 7.45-7.28 (d, J = 6.06 Hz, 2H), 4.47-4.46(s, 2H), 4.05 (s, 4H), 3.18-3.14 (m, 2H), 2.06-1.96 (m, 4H). mGluR5 PAMEC₅₀: ++++. Fold shift at 10 μM: ++. Example 7.13

Method B; MS (ESI): 392; ¹H NMR (300 MHz, CDCl₃) δ 8.53-8.52 (d, J =6.03 Hz, 1H), 8.27- 8.24 (d, J = 8.25 Hz, 1H), 7.83 (s, 1H), 7.63-7.59(m, 2H), 7.49-7.28 (m, 1H), 4.46-4.44 (m, 2H), 4.05 (s, 4H), 3.18-3.14(m, 2H), 2.06-1.95 (m, 4H). mGluR5 PAM EC₅₀: +++. Example 7.14

Method B; MS (ESI): 392; ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.23 (d, J =8.61 Hz, 2H), 8.00- 7.94 (m, 1H), 7.81 (s, 1H), 7.61-7.58 (dd, J = 8.24,1.52 Hz, 1H), 7.28-7.24 (m, 1H), 4.46-4.44 (m, 2H), 4.05 (s, 4H),3.17-3.14 (m, 2H), 2.06- 1.96 (m, 4H). mGluR5 PAM EC₅₀: ++. Example 7.15

Method B; MS (ESI): 392; ¹H NMR (300 MHz, CDCl₃) δ 8.45 (s, 1H),8.27-8.24 (d, J = 8.19 Hz, 1H), 8.00-7.93 (m, 1H), 7.78 (s, 1H),7.58-7.54 (dd, J = 8.22, 1.50 Hz, 1H), 7.01-6.97 (m, 1H), 4.46-4.43 (m,2H), 4.05 (s, 4H), 3.17-3.14 (m, 2H), 2.06-1.96 (m, 4H). mGluR5 PAMEC₅₀: +++. Fold shift at 10 μM: +++. Example 7.16

Method B; MS (ESI): 392; ¹H NMR (300 MHz, CDCl₃) δ 8.52 (s, 1H),8.27-8.24 (d, J = 8.22 Hz, 1H), 7.83 (s, 1H), 7.70-7.59 (m, 2H),7.51-7.42 (m, 1H), 4.47-4.46 (m, 2H), 4.05 (s, 4H), 3.17- 3.14 (m, 2H),2.06-1.95 (m, 4H). mGluR5 PAM EC₅₀: ++. Example 7.17

Method B; MS (ESI): 392; ¹H NMR (300 MHz, CDCl₃) δ 8.29-8.25 (m, 2H),7.80 (s, 1H), 7.80- 7.56 (dd, J = 8.21, 1.55 Hz, 1H), 7.34-7.28 (m, 1H),7.09 (s, 1H), 4.47-4.46 (m, 2H), 4.05 (s, 4H), 3.18-3.14 (m, 2H),2.06-1.95 (m, 4H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.Example 7.18

Method B; MS (ESI): 416; ¹H NMR (300 MHz, CDCl₃) δ 8.27-8.25 (d, J =6.00 Hz, 1H), 7.89 (s, 1H), 7.85-7.62 (m, 2H), 7.44-7.25 (m, 2H), 4.55-4.31 (m, 2H), 4.05 (s, 4H), 3.17-3.14 (m, 2H), 2.06-1.97 (m, 4H).Example 7.19

Method B; MS (ESI): 416; ¹H NMR (300 MHz, CDCl₃) δ 8.27-8.25 (d, J =8.16 Hz, 1H), 7.86- 7.76 (m, 3H), 7.57-7.54 (dd, J = 8.22 Hz, 1H),7.27-7.24 (m, 1H), 4.48-4.44 (m, 2H), 4.05 (s, 4H), 3.17-3.14 (m, 2H),2.07-1.96 (m, 4H). mGluR5 PAM EC₅₀: +. Example 7.20

Method B; MS (ESI): 416; ¹H NMR (300 MHz, CDCl₃) δ 8.28-8.26 (d, J =7.83 Hz, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.57-7.50 (m, 2H), 7.39-7.37(m, 1H), 4.45-4.46 (m, 2H), 4.05 (s, 4H), 3.17- 3.14 (m, 2H), 2.06-1.96(m, 4H). Example 7.21

Method B; MS (ESI): 416; ¹H NMR (300 MHz, CDCl₃) δ 8.28-8.26 (d, J =8.28 Hz, 1H), 7.83 (s, 1H), 7.70-7.67 (m, 1H), 7.61-7.57 (m, 1H), 7.50-7.43 (m, 2H), 4.46-4.45 (m, 2H), 4.05 (s, 4H), 3.17-3.14 (m, 2H),2.06-1.98 (m, 4H). Example 7.22

Method B; MS (ESI): 375; ¹H NMR (300 MHz, CDCl₃) δ 8.82-8.80 (d, J =4.93 Hz, 2H), 8.28- 8.86 (d, J = 8.34 Hz, 1H), 7.91 (s, 1H), 7.78-7.67(d, J = 8.24 Hz, 1H), 7.33-7.29 (m, 1H), 4.46-4.40 (m, 2H), 4.05 (s,4H), 3.28-3.13 (m, 2H), 2.06- 1.96 (m, 4H). Example 7.23

Method B; MS (ESI): 375; ¹H NMR (300 MHz, CDCl₃) δ 9.27 (s, 1H),8.80-8.79 (d, J = 5.13 Hz, 1H), 8.29-8.26 (d, J = 8.22 Hz, 1H), 7.86 (s,1H), 7.65-7.62 (dd, J = 8.25, 1.50 Hz, 1H), 7.54-7.52 (dd, J = 5.15,1.40 Hz, 4H), 4.46-4.45 (m, 2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H),2.06-1.67 (m, 4H). Example 7.24

Method B; MS (ESI): 375; ¹H NMR (300 MHz, CDCl₃) δ 8.83 (s, 1H), 8.64(s, 1H), 8.56 (s, 1H), 8.56-8.27 (d, J = 8.25 Hz, 1H), 7.87 (s, 1H),7.66- 7.63 (dd, J = 8.24, 1.55 Hz, 1H), 4.46-4.45 (m, 2H), 4.05 (s, 4H),3.18-3.14 (m, 2H), 2.06-1.66 (m, 4H). Example 7.25

Method B; MS (ESI): 375; ¹H NMR (300 MHz, CDCl₃) δ 9.20 (s, 1H), 8.92(s, 2H), 8.29-8.26 (d, J = 8.24 Hz, 1H), 7.68 (s, 1H), 7.60-7.57 (dd, J= 8.24, 1.54 Hz, 1H), 4.48-4.46 (m, 2H), 4.05 (s, 4H), 3.18-3.14 (m,2H), 2.06-1.96 (m, 4H). Example 7.26

Method B; MS (ESI): 389; ¹H NMR (300 MHz, CDCl₃) δ 8.82 (s, 2H),8.28-8.25 (d, J = 7.83 Hz, 1H), 7.79 (s, 1H), 7.59-7.56 (dd, J = 8.25,1.53 Hz, 1H), 4.46-4.44 (m, 2H), 4.05 (s, 4H), 3.17- 3.13 (m, 2H), 2.80(s, 3H), 2.06-1.96 (m, 4H). Example 7.27

Method B; MS (ESI): 421; ¹H NMR (300 MHz, CDCl₃) δ 8.66 (s, 2H),8.27-8.24 (dd, J = 8.25, 0.45 Hz, 1H), 7.77 (s, 1H), 7.58-7.55 (dd, J =8.24, 1.55 Hz, 1H), 4.48-4.46 (m, 2H), 4.05 (s, 4H), 2.62 (s, 3H),3.17-3.13 (m, 2H), 2.06-1.96 (m, 4H). Example 7.28

Method B; MS (ESI): 405; ¹H NMR (300 MHz, CDCl₃) δ 8.71 (s, 2H),8.27-8.24 (dd, J = 7.78, 0.48 Hz, 1H), 7.67 (s, 1H), 7.58-7.54 (dd, J =8.22, 1.56 Hz, 1H), 4.45-4.41 (m, 2H), 4.08 (s, 3H), 4.05 (s, 4H),3.17-3.13 (m, 2H), 2.06-1.96 (m, 4H). Example 7.29

Method B; MS (ESI): 418; ¹H NMR (300 MHz, CDCl₃) δ 8.49 (s, 2H),8.24-8.21 (d, J = 8.25 Hz, 1H), 7.72 (s, 1H), 7.55-7.52 (dd, J = 8.25,1.54 Hz, 1H), 4.46-4.45 (m, 2H), 4.05 (s, 4H), 3.25 (s, 6H), 3.17-3.13(m, 2H), 2.06-1.96 (m, 4H). Example 7.30

Method A; MS (ESI): 387; ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.23 (d, J =8.28 Hz, 1H), 7.79 (s, 1H), 7.59-7.53 (t, J = 8.15 Hz, 2H), 7.29-7.28(m, 1H), 7.26-7.25 (m, 1H), 7.23-7.19 (m, 1H), 4.47- 4.46 (m, 2H), 4.05(s, 4H), 3.17-3.13 (m, 2H), 2.55 (s, 3H), 2.06-1.96 (m, 4H). Example7.31

Method A; MS (ESI): 387; ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.22 (d, J =8.25 Hz, 1H), 7.76 (s, 1H), 7.57-7.55 (dd, J = 8.25, 1.50 Hz, 1H), 7.41-7.38 (m, 2H), 7.28-7.25 (m, 1H), 7.21-7.19 (m, 1H), 4.45-4.46 (m, 2H),4.05 (s, 4H), 3.17-3.13 (m, 2H), 2.39 (s, 3H), 2.39-1.96 (m, 4H). mGluR5PAM EC₅₀: ++. Fold shift at 10 μM: +++. Example 7.32

Method A; MS (ESI): 387; ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.13 (d, J =8.31 Hz, 1H), 7.88 (s, 1H), 7.57-7.54 (dd, J = 8.27, 1.55 Hz, 1H), 7.49-7.46 (m, 2H), 7.21-7.19 (d, J = 7.98 Hz, 2H), 4.49-4.45 (m, 2H), 4.05(s, 4H), 3.17-3.13 (m, 2H), 2.46 (s, 3H), 2.06-2.02 (m, 2H), 1.99-1.96(m, 2H). mGluR5 PAM EC₅₀: +. Example 7.33

Method A; MS (ESI): 401; ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.21 (d, J =8.10 Hz, 1H), 7.76 (s, 1H), 7.58-7.54 (dd, J = 8.27, 1.52 Hz, 1H), 7.52-7.49 (d, J = 8.16 Hz, 2H), 7.24-7.21 (d, J = 8.22 Hz, 2H), 4.45-4.44 (m,2H), 4.05 (s, 4H), 3.17- 3.13 (m, 2H), 2.73-2.66 (m, 2H), 2.06-1.96 (m,4H), 1.30-1.24 (t, J = 7.59 Hz, 3H). Example 7.34

Method A; MS (ESI): 403; ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.21 (d, J =8.28 Hz, 1H), 7.80 (s, 1H), 7.61-7.58 (d, J = 7.85 Hz, 1H), 7.55-7.52(d, J = 7.85 Hz, 1H), 7.39-7.33 (t, J = 8.22 Hz, 1H), 7.00-6.93 (m, 2H),4.48-4.46 (m, 2H), 4.05 (s, 4H), 3.95 (s, 3H), 3.17-3.13 (m, 2H),2.06-1.96 (m, 4H). Example 7.35

Method A; MS (ESI): 403; ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.22 (d, J =8.28 Hz, 1H), 7.78 (s, 1H), 7.59-7.55 (d, J = 8.22 Hz, 1H), 7.33-7.30(m, 1H), 7.19-7.17 (dd, J = 8.10, 1.86 Hz, 1H), 7.10 (s, 1H), 6.97-6.93(m, 1H), 4.46-4.45 (m, 2H), 4.05 (s, 4H), 3.86 (s, 3H), 3.17-3.13 (m,2H), 2.06-1.96 (m, 4H). Example 7.36

Method A; MS (ESI): 403; ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.20 (d, J =8.25 Hz, 1H), 7.75 (s, 1H), 7.56-7.53 (dd, J = 8.35, 1.53 Hz, 1H), 7.38-7.36 (d, J = 4.38 Hz, 2H), 6.94-6.91 (m, 2H), 4.47-4.46 (m, 2H), 4.05(s, 4H), 3.86 (s, 3H), 3.17-3.13 (m, 2H), 2.06-1.95 (m, 4H). Example7.37

Method A; MS (ESI): 398; ¹H NMR (300 MHz, CDCl₃) δ 8.28-8.25 (d, J =7.80 Hz, 1H), 7.87 (s, 1H), 7.74-7.68 (m, 2H), 7.67-7.59 (m, 2H), 7.51-7.45 (m, 1H), 4.46-4.41 (m, 2H), 4.05 (s, 4H), 3.17-3.14 (m, 2H),2.06-1.96 (m, 4H). Example 7.38

Method B; MS (ESI): 398; ¹H NMR (300 MHz, CDCl₃) δ 8.28-8.25 (d, J =8.25 Hz, 1H), 7.86 (s, 1H), 7.81-7.80 (m, 2H), 7.78-7.65 (m, 1H), 7.58-7.28 (m, 2H), 4.49-4.46 (m, 2H), 4.05 (s, 4H), 3.18-3.14 (m, 2H),2.06-1.96 (m, 4H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.Example 7.39

MS (ESI): 398; ¹H NMR (300 MHz, CDCl₃) δ 8.27-8.25 (d, J = 8.16 Hz, 1H),7.82 (s, 1H), 7.67 (broad, 4H), 7.58-7.28 (m, 1H), 4.46-4.45 (m, 2H),4.05 (s, 4H), 3.53-3.46 (m, 2H), 2.06-1.90 (m, 4H). mGluR5 PAM EC₅₀: +.Example 7.40

Method A; MS (ESI): 441; ¹H NMR (300 MHz, CDCl₃) δ 8.27-8.24 (d, J =8.25 Hz, 1H), 7.82 (s, 1H), 7.74-7.71 (d, J = 8.70 Hz, 2H), 7.60-7.55(dd, J = 8.22, 1.47 Hz, 2H), 7.55-7.50 (d, J = 11.89 Hz, 1H), 4.46-4.41(m, 2H), 4.05 (s, 4H), 3.18-3.14 (m, 2H), 2.06-1.96 (m, 4H). mGluR5 PAMEC₅₀: ++. Example 7.41

Method A; MS (ESI): 441; ¹H NMR (300 MHz, CDCl₃) δ 8.27-8.24 (d, J =8.28 Hz, 1H), 7.85 (s, 1H), 7.78-7.74 (m, 2H), 7.65-7.50 (m, 3H), 4.46-4.45 (m, 2H), 4.05 (s, 4H), 3.17-3.14 (m, 2H), 2.06-1.96 (m, 4H).Example 7.42

Method A; MS (ESI): 441; ¹H NMR (300 MHz, CDCl₃) δ 8.27-8.24 (d, J =8.31 Hz, 1H), 7.79 (s, 1H), 7.71-7.63 (m, 4H), 7.60-7.56 (dd, J = 8.25,1.44 Hz, 1H), 4.46-4.41 (m, 2H), 4.05 (s, 4H), 3.17-3.14 (m, 2H),2.06-1.96 (m, 4H). Example 7.43

Method B; MS (ESI): 388; ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.23 (m, 1H),8.22-8.20 (d, J = 8.25 Hz, 1H), 7.80-7.75 (m, 2H), 7.56-7.53 (dd, J =7.59, 2.70 Hz, 1H), 7.18-7.13 (m, 1H), 4.44-4.43 (m, 2H), 4.03 (s, 4H),3.15-3.11 (m, 2H), 2.77 (s, 3H), 2.10-1.94 (m, 4H). Example 7.44

Method B; MS (ESI): 388; ¹H NMR (300 MHz, CDCl₃) δ 8.55 (s, 1H),8.48-8.46 (d, J = 5.10 Hz, 1H), 8.28-8.26 (d, J = 8.22 Hz, 1H), 7.81 (s,1H), 7.60-7.57 (d, J = 8.24 Hz, 1H), 7.39-7.38 (d, J = 4.98 Hz, 1H),4.46 (s, 2H), 4.05 (s, 4H), 3.18-3.14 (m, 2H), 2.51 (s, 3H), 2.06-1.96(m, 4H). Example 7.45

Method B; MS (ESI): 388; ¹H NMR (300 MHz, CDCl₃) δ 8.72 (s, 1H),8.46-8.44 (m, 1H), 8.26- 8.24 (d, J = 6.00 Hz, 1H), 7.80 (s, 1H),7.59-7.55 (d, J = 12.00 Hz, 1H), 7.28-7.19 (m, 1H), 4.46- 4.45 (m, 2H),4.04 (s, 4H), 3.17-3.13 (m, 2H), 2.54 (s, 3H), 2.11-1.95 (m, 4H).Example 7.46

Method B; MS (ESI): 388; (300 MHz, CDCl₃) δ 8.25-8.23 (dd, J = 8.24,0.41 Hz, 1H), 7.84 (s, 1H), 7.65-7.59 (m, 2H), 7.43-7.40 (d, J = 7.68Hz, 1H), 7.18-7.16 (d, J = 7.32 Hz, 1H), 4.45-4.44 (m, 2H), 4.04 (s,4H), 3.17-3.13 (m, 2H), 2.62 (s, 3H), 2.06-1.95 (m, 4H). mGluR5 PAMEC₅₀: ++. Example 7.47

Method B; MS (ESI): 388; ¹H NMR (300 MHz, CDCl₃) δ 8.53-8.51 (d, J =5.10 Hz, 1H), 8.26- 8.23 (d, J = 8.22 Hz, 1H), 7.78 (s, 1H), 7.57-7.54(dd, J = 8.24, 1.46 Hz, 1H), 7.31-7.28 (d, J = 9.33 Hz, 1H), 7.25-7.23(d, J = 5.10 Hz, 1H), 4.45-4.44 (m, 2H), 4.04 (s, 4H), 3.16-3.12 (m,2H), 2.59 (s, 3H), 2.06-1.95 (m, 4H). mGluR5 PAM EC₅₀: ++++. Fold shiftat 10 μM: +++. Example 7.48

Method B; MS (ESI): 388; ¹H NMR (300 MHz, CDCl₃) δ 8.52-8.50 (d, J =5.04 Hz, 1H), 8.26- 8.23 (d, J = 8.25 Hz, 1H), 7.82 (s, 1H), 7.64-7.60(dd, J = 8.24, 1.43 Hz, 1H), 7.43 (s, 1H), 7.11 (m, 1H), 4.45-4.44 (m,2H), 4.04 (s, 4H), 3.17-3.13 (m, 2H), 2.40 (s, 3H), 2.12-1.95 (m, 4H).mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++. Example 7.49

Method B; MS (ESI): 399; ¹H NMR (300 MHz, CDCl₃) δ 8.86-8.85 (dd, J =4.92, 1.77 Hz, 1H), 8.30-8.27 (d, J = 8.22 Hz, 1H), 8.05-8.01 (dd, J =7.98, 1.71 Hz, 1H), 7.96 (s, 1H), 7.89-7.82 (m, 1H), 7.73-7.66 (dd, J =7.97, 4.94 Hz, 2H), 7.44- 7.40 (m, 1H), 7.38-7.31 (m, 2H), 7.22-7.17 (m,1H), 4.47-4.46 (m, 2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H), 2.06-1.96 (m,4H). mGluR5 PAM EC₅₀: +. Example 7.50

Method B; MS (ESI): 399; ¹H NMR (300 MHz, CDCl₃) δ 8.86-8.85 (dd, J =4.92, 1.77 Hz, 1H), 8.30-8.27 (d, J = 8.22 Hz, 1H), 8.05-8.01 (dd, J =7.98, 1.71 Hz, 1H), 7.96 (s, 1H), 7.89-7.82 (m, 1H), 7.73-7.66 (dd, J =7.97, 4.94 Hz, 2H), 7.44- 7.40 (m, 1H), 7.38-7.31 (m, 2H), 7.22-7.17 (m,1H), 4.47-4.46 (m, 2H), 4.05 (s, 4H), 3.17-3.13 (m, 2H), 2.06-1.96 (m,4H) Example 7.51

Method B; MS (ESI): 363; ¹H NMR (300 MHz, CDCl₃) δ 8.20-8.17 (d, J = 8.3Hz, 1H), 7.67-7.66 (d, J = 1.0 Hz, 1H), 7.49-7.46 (dd, J = 8.3, 1.4 Hz,1H), 6.25-6.24 (t, J = 2.1 Hz, 1H), 4.44 (broad, 2H), 4.04 (s, 4H),3.15-3.11 (t, J = 5.4 Hz, 2H), 2.62-2.49 (m, 4H), 2.05-1.94 (m, 6H).mGluR5 PAM EC₅₀: ++. Example 7.52

Method A; MS (ESI): 365; ¹H NMR (300 MHz, CDCl₃) δ 8.17-8.14 (d, J = 8.2Hz, 1H), 7.61 (s, 1H), 7.44-7.41 (dd, J = 8.2, 1.5 Hz, 1H), 4.43 (broad,2H), 4.06 (s, 4H), 3.14-3.11 (t, J = 5.7 Hz, 2H), 2.90-2.86 (m, 1H),2.04-1.94 (m, 6H), 1.83- 1.74 (m, 4H), 1.67-1.61 (m, 2H). mGluR5 PAMEC₅₀: +. Example 7.53

Method B; MS (ESI): 377; ¹H NMR (300 MHz, CDCl₃) δ 8.19-8.16 (d, J = 8.2Hz, 1H), 7.65 (s, 1H), 7.47-7.44 (dd, J = 8.2, 1.5 Hz, 1H), 6.32- 6.29(m, 1H), 4.43 (broad, 2H), 4.07 (s, 4H), 3.15- 3.11 (t, J = 5.7 Hz, 2H),2.26-2.18 (m, 4H), 2.05- 1.94 (m, 4H), 1.73-1.61 (m, 4H). mGluR5 PAMEC₅₀: +. Fold shift at 10 μM: ++. Example 7.54

Method A; MS (ESI): 379; ¹H NMR (300 MHz, CDCl₃) δ 8.17-8.11 (d, J = 8.2Hz, 1H), 7.81 (s, 1H), 7.45-7.42 (dd, J = 8.2, 1.5 Hz, 1H), 4.43 (broad,2H), 4.04 (s, 4H), 3.15-3.11 (t, J = 5.7 Hz, 2H), 2.70-2.61 (m, 1H),2.08-1.88 (m, 6H), 1.81- 1.76 (m, 2H) 1.58-1.53 (m, 2H), 1.38-1.35 (m,2H). mGluR5 PAM EC₅₀: +. Example 7.55

Method B; MS (ESI): 363; ¹H NMR (300 MHz, CDCl₃) δ 8.26-8.22 (d, J = 8.2Hz, 1H), 7.75-7.74 (d, J = 1.1 Hz, 1H), 7.57-7.54 (dd, J = 8.2, 1.5 Hz,1H), 7.49-7.48 (d, J = 1.3, 1H), 6.77-6.76 (d, 3.2 Hz, 1H), 6.49-6.47(dd, J = 3.4 Hz, 1.9 Hz, 1H), 4.45 (broad, 2H), 4.050 (s, 4H), 3.16-3.12(t, J = 5.7 Hz, 2H), 2.06-2.03 (t, J = 5.4 Hz, 2H), 1.98- 1.95 (t, J =5.1 Hz, 2H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++. Example7.56

Method B; MS (ESI): 363; ¹H NMR (300 MHz, CDCl₃) δ 8.23-8.21 (d, J = 8.1Hz, 1H), 7.76-7.72 (d, J = 12.7 Hz, 2H), 7.54-7.51 (dd, J = 8.2, 1.3 Hz,1H), 7.45-7.44 (d, J = 1.5 Hz, 1H), 6.58-6.57 (d, J = 1.3 Hz, 1H), 4.45(s, 2H), 4.05 (s, 4H), 3.16-3.12 (t, J = 5.7 Hz, 2H), 2.05-2.02 (t, J =5.4 Hz, 2H), 1.98-1.95 (t, J = 5.1 Hz, 2H). mGluR5 PAM EC₅₀: +++.Example 7.57

Method A; MS (ESI): 379; ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.22 (d, J = 8.2Hz, 1H), 7.74-7.73 (d, J = 1.2 Hz, 1H), 7.56-7.53 (dd, J = 8.3, 1.5 Hz,1H), 7.38-7.36 (d, J = 4.4 Hz, 2H), 7.07-7.05 (m, 1H), 4.46 (broad, 2H),4.05 (s, 4H), 3.17-3.13 (t, J = 5.7 Hz, 2H), 2.06-2.02 (t, J = 5.4 Hz,2H), 1.99- 1.95 (t, J = 5.1 Hz, 2H). mGluR5 PAM EC₅₀: +++. Fold shift at10 μM: ++. Example 7.58

Method B; MS (ESI): 393; ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.20 (d, J = 8.2Hz, 1H), 7.75 (s, 1H), 7.56-7.50 (dd, J = 8.2, 1.5 Hz, 1H), 7.26- 7.24(d, J = 5.1 Hz, 1H), 6.92-6.91 (d, J = 5.1 Hz, 1H), 4.51 (broad, 2H),4.05 (s, 4H), 3.17-3.13 (t, J = 5.7 Hz, 2H), 2.42 (s, 3H), 2.06-2.02 (t,J = 5.4 Hz, 2H), 1.99-1.95 (t, J = 5.1 Hz, 2H). mGluR5 PAM EC₅₀: +.Example 7.59

Method A; MS (ESI): 379; ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.21 (d, J = 8.2Hz, 1H), 7.74 (s, 1H), 7.62-7.61 (dd, J = 3.0, 1.1 Hz, 1H), 7.56- 7.53(dd, J = 8.2, 1.5 Hz, 1H), 7.36-7.33 (m, 1H), 7.28-7.24 (m, 1H), 4.46(broad, 2H), 4.05 (s, 4H), 3.17-3.13 (t, J = 5.7 Hz, 2H), 2.06-2.02 (t,J = 5.4 Hz, 2H), 1.99-1.95 (t, J = 5.1 Hz, 2H). mGluR5 PAM EC₅₀: ++++.Fold shift at 10 μM: ++. Example 7.60

Method B; MS (ESI): 380; ¹H NMR (300 MHz, CDCl₃) δ 8.28-8.25 (d, J = 8.4Hz, 1H), 7.93 (d, J = 3.3 Hz, 1H), 7.84 (s, 1H), 7.64-7.61 (dd, J = 8.2,1.6 Hz, 1H), 7.46-7.45 (d, J = 3.3 Hz, 1H), 4.45 (broad, 2H), 4.05 (s,4H), 3.17-3.13 (t, J = 5.7 Hz, 2H), 2.06-2.02 (t, J = 5.4 Hz, 2H), 1.99-1.95 (t, J = 5.1 Hz, 2H). mGluR5 PAM EC₅₀: +. Example 7.61

Method B; MS (ESI): 394; ¹H NMR (300 MHz, CDCl₃) δ 8.27-8.24 (d, J = 8.3Hz, 1H), 7.82 (s, 1H), 7.62-7.59 (dd, J = 8.3, 1.4 Hz, 1H), 7.01 (s,1H), 4.45 (broad, 2H), 4.04 (s, 4H), 3.17-3.13 (t, J = 5.7 Hz, 2H), 2.53(s, 3H), 2.06-2.02 (t, J = 5.4 Hz, 2H), 1.99-1.95 (t, J = 5.1 Hz, 2H).mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++. Example 7.62

Method B; MS (ESI): 380; ¹H NMR (300 MHz, CDCl₃) δ 8.60 (s, 1H),8.26-8.23 (d, J = 8.1 Hz, 1H), 7.81 (s, 1H), 7.68 (s, 1H), 7.62-7.60(dd, J = 8.3, 1.4 Hz, 1H), 4.45 (broad, 2H), 4.05 (s, 4H), 3.17-3.13 (t,J = 5.7 Hz, 2H), 2.06-2.02 (t, J = 5.4 Hz, 2H), 1.99-1.95 (t, J = 5.1Hz, 2H). mGluR5 PAM EC₅₀: +. Example 7.63

Method B; MS (ESI): 394; ¹H NMR (300 MHz, CDCl₃) δ 8.69 (s, 1H),8.26-8.23 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 1.2 Hz, 1H), 7.56-7.52 (dd,J = 8.3, 1.5 Hz, 1H), 4.45 (broad, 2H), 4.03 (s, 4H), 3.15-3.11 (t, J =5.7 Hz, 2H), 2.63 (s, 3H), 2.06- 2.02 (t, J = 5.4 Hz, 2H), 1.99-1.95 (t,J = 5.1 Hz, 2H). mGluR5 PAM EC₅₀: +. Example 7.64

Method B; MS (ESI): 380; ¹H NMR (300 MHz, CDCl₃) δ 8.81 (s, 1H),8.27-8.24 (d, J = 8.3 Hz, 1H), 8.13 (s, 1H), 7.76 (s, 1H), 7.57-7.54(dd, J = 7.7, 2.4 Hz, 1H), 4.45 (broad, 2H), 4.05 (s, 4H), 3.17-3.13 (t,J = 5.7 Hz, 2H), 2.06-2.02 (t, J = 5.4 Hz, 2H), 1.99-1.95 (t, J = 5.1Hz, 2H). Example 7.65

Method B; MS (ESI): 377; ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.21 (d, J = 8.2Hz, 1H), 7.78 (s, 1H), 7.59-7.56 (dd, J = 8.2, 1.4 Hz, 1H), 7.15- 7.08(broad, 1H), 6.98 (s, 1H), 4.43 (broad, 2H), 4.03 (s, 4H), 3.82 (s, 3H),3.15-3.11 (t, J = 5.7 Hz, 2H), 2.04-2.00 (t, J = 5.4 Hz, 2H), 1.97-1.93(t, J = 5.1 Hz, 2H). Example 7.66

Method A; MS (ESI): 377; ¹H NMR (300 MHz, CDCl₃) δ 8.26-8.23 (d, J = 8.2Hz, 1H), 7.74 (s, 1H), 7.54-7.50 (m, 2H), 7.45-7.42 (m, 1H), 4.45(broad, 2H), 4.05 (s, 4H), 3.78 (s, 3H), 3.17-3.13 (t, J = 5.7 Hz, 2H),2.06-2.02 (t, J = 5.4 Hz, 2H), 1.99-1.95 (t, J = 5.1 Hz, 2H). Example7.67

Method A; MS (ESI): 392; ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.22 (d, J = 8.3Hz, 1H), 7.74-7.74 (d, J = 1.3 Hz, 1H), 7.54-7.51 (dd, J = 8.2, 1.4 Hz,1H), 4.45 (broad, 2H), 4.05 (s, 4H), 3.17-3.13 (t, J = 5.7 Hz, 2H), 2.55(s, 3H), 2.38 (s, 3H), 2.06- 2.02 (t, J = 5.4 Hz, 2H), 1.99-1.95 (t, J =5.1 Hz, 2H). mGluR5 PAM EC₅₀: ++++. Example 7.68

Method B; MS (ESI): 378; ¹H NMR (300 MHz, CDCl3) δ 8.28-8.27 (d, J = 8.3Hz, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.63-7.60 (d, J = 8.2 Hz, 1H), 4.48(broad, 2H), 4.06-4.05 (d, 7H), 3.17-3.13 (t, J = 5.7 Hz, 2H), 2.06-2.02(t, J = 5.4 Hz, 2H), 1.99-1.95 (t, J = 5.1 Hz, 2H). Example 7.69

Method B; MS (ESI): 377; ¹H NMR (300 MHz, CDCl₃) δ 8.22-8.19 (d, J = 8.3Hz, 1H), 7.70 (s, 2H), 7.62 (s, 1H), 7.53-7.49 (dd, J = 8.2, 1.4 Hz,1H), 4.44 (broad, 2H), 4.05 (s, 4H), 3.95 (s, 3H), 3.16-3.12 (t, J = 5.7Hz, 2H), 2.05-2.01 (t, J = 5.4 Hz, 2H), 1.98-1.94 (t, J = 5.1 Hz, 2H).mGluR5 PAM EC₅₀: ++.

Example 8.1 Synthesis of8-((4-fluorophenyl)ethynyl)-3-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

Example 8.1a Synthesis of8-bromo-3-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.21d.

Example 8.1b Synthesis of8-((4-fluorophenyl)ethynyl)-3-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 348 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.24-8.20 (d, J=6.54 Hz, 1H), 7.75 (s, 1H), 7.56 (m, 3H), 7.08(m, 2H), 4.56 (m, 2H), 3.22 (m, 2H), 2.78-2.72 (m, 4H), 2.40 (s, 3H).mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM: ++.

Example 8.2 Synthesis of3-ethyl-8-((4-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

Example 8.2a Synthesis of8-bromo-3-ethyl-2,3,4,5-tetrahydro-[1,4]diazepino-[7,1-b]quinazolin-11(1H)-one

A solution of8-bromo-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one(100 mg, 0.34 mmol), K₂CO₃ (188 mg, 1.36 mmol) and excess iodoethane inacetone (20 mL) was stirred at room temperature overnight. Then thereaction mixture was diluted with water (80 mL) and extracted with ethylacetate (3×70 mL). The combined organic layers were dried over Na₂SO₄.After filtration and concentration, the residue was purified by silicagel chromatography to give 100 mg of the desired product. MS (ESI): 322,324 (MH⁺).

Example 8.2b Synthesis of3-ethyl-8-((4-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 362 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.25-8.22 (d, J=8.25 Hz, 1H), 7.76 (s, 1H), 7.60-7.54 (m, 3H),7.12-7.06 (d, J=8.72 Hz, 2H), 4.53-4.51 (m, 2H), 3.25-3.22 (m, 2H),2.84-2.77 (m, 4H), 2.62-2.55 (q, J=7.2 Hz, 2H), 1.15-1.10 (t, J=7.1 Hz,3H). mGluR5 PAM EC₅₀: ++.

Example 8.3 Synthesis of8-((4-fluorophenyl)ethynyl)-3-isopropyl-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 8.2a and Example 1.1. MS (ESI): 376 (MH⁺); ¹HNMR (300 MHz, CD₃OD) δ 8.25-8.22 (d, J=8.28 Hz, 1H), 7.75 (s, 1H),7.59-7.54 (m, 3H), 7.12-7.07 (t, J=8.72 Hz, 2H), 4.51-4.49 (m, 2H),3.23-3.19 (m, 2H), 3.03-2.94 (m, 1H), 2.88-2.79 (m, 4H), 1.06-1.04 (d,J=6.66 Hz, 6H). mGluR5 PAM EC₅₀: ++.

Example 8.4 Synthesis of8-((4-fluorophenyl)ethynyl)-3,3-dimethyl-11-oxo-1,2,3,4,5,11-hexahydro-[1,4]diazepino[7,1-b]quinazolin-3-ium

To a solution of8-((4-fluorophenyl)ethynyl)-3-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one(6.2 mg, 0.018 mmol) in CH₃CN (1 mL) at room temperature was added MeI(20 μL). The resulting mixture was stirred overnight. LC-Mass analysisindicated the reaction was complete. Solvent and excess methyl iodidewas removed by evaporation. MS (ESI): 362.4 (MH⁺).

Example 8.5 Synthesis of tert-butyl8-((3-fluorophenyl)ethynyl)-11-oxo-1,2,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazoline-3(11H)-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 434 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.26-8.23 (d, J=8.2 Hz, 1H), 7.78 (s, 1H),7.60-7.56 (dd, J=8.3, 1.5 Hz, 1H), 7.38-7.35 (m, 2H), 7.29-7.28 (m, 1H),7.13-7.08 (m, 1H), 4.50-4.48 (t, J=4.2 Hz, 2H), 3.83-3.80 (t, J=4.5 Hz,2H), 3.76-3.74 (t, J=3.9 Hz, 2H), 3.22-3.19 (t, J=5.1 Hz, 2H), 1.51 (s,9H).

Example 8.6 Synthesis of8-((3-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

To a solution oftert-butyl-8-(2-(3-fluorophenyl)ethynyl)-11-oxo-1,2,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazoline-3(11H)-carboxylate(1.3 g, 3.0 mmol) in DCM (30 mL) was added trifluoroacetic acid (15 mL).The mixture was stirred for 1 h at room temperature. Then the reactionmixture was concentrated and purified by silica gel chromatography togive the desired product. MS (ESI): 334 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ8.26-8.23 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.59-7.55 (d, J=8.3 Hz, 1.5Hz, 1H), 7.38-7.34 (m, 2H), 7.29-7.26 (m, 1H), 7.14-7.09 (m, 1H),4.53-4.50 (t, J=3.6 Hz, 2H), 3.24-3.17 (m, 4H), 3.11-3.10 (t, J=4.5 Hz,2H). mGluR5 PAM EC₅₀: ++.

Example 8.7 Synthesis of8-((3-fluorophenyl)ethynyl)-3-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 8.2a. MS (ESI): 348 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.25-8.22 (d, J=8.16 Hz, 1H), 7.77 (s, 1H), 7.58-7.55 (dd,J=8.22, J=1.41 Hz, 1H), 7.37-7.34 (m, 2H), 7.32-7.28 (m, 1H), 7.14-7.07(m, 1H), 4.52 (m, 2H), 3.30-3.22 (m, 2H), 2.80-2.72 (m, 4H), 2.41 (s,3H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++.

Example 8.8 Synthesis of8-((3-fluorophenyl)ethynyl)-3-propyl-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 8.2a. MS (ESI): 376 MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.26-8.23 (d, J=8.25 Hz, 1H), 7.77 (s, 1H), 7.59-7.55 (d,J=8.25 Hz, 1.51 Hz, 1H), 7.38-7.35 (m, 2H), 7.29-7.28 (m, 1H), 7.12-7.08(m, 1H), 4.53-4.52 (m, 2H), 3.25-3.21 (m, 2H), 2.84-2.75 (m, 4H),2.48-2.43 (t, J=7.35 Hz, 2H), 1.62-1.51 (m, 2H), 0.96-0.91 (t, J=7.34Hz, 3H). mGluR5 PAM EC₅₀: ++.

Example 8.9 Synthesis of3-benzyl-8-((3-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 8.2a. MS (ESI): 424(MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.25-8.22 (d, J=8.22 Hz, 1H), 7.76 (s, 1H), 7.58-7.55 (dd,J=8.22, 1.35 Hz, 1H), 7.40-7.32 (m, 7H), 7.28-7.26 (m, 1H), 7.13-7.07(m, 1H), 4.52-4.51 (m, 2H), 3.65 (s, 2H), 3.24-3.21 (m, 2H), 2.84-2.77(m, 4H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: ++.

Example 8.10 Synthesis of8-((3-fluorophenyl)ethynyl)-3-(2-methoxyethyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 8.2a. DMF was used as the solvent. MS (ESI): 392(MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.26-8.23 (d, J=8.3 Hz, 1H), 7.77 (s,1H), 7.59-7.55 (d, J=8.3 Hz, 1.5 Hz, 1H), 7.38-7.34 (m, 2H), 7.30-7.26(m, 1H), 7.12-7.08 (m, 1H), 4.55-4.52 (m, 2H), 3.57-3.51 (t, J=5.4 Hz,2H), 3.39 (s, 3H), 3.25-3.19 (m, 2H), 2.92-2.83 (m, 4H), 2.76-2.73 (t,J=5.4 Hz, 2H). mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM: ++.

Example 8.11 Synthesis of3-cyclobutyl-8-((3-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 8.2a. DMF was used as the solvent. MS (ESI): 388(MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.34-8.32 (d, J=8.16 Hz, 1H), 7.89-7.82(m 2H), 7.59-7.45 (m, 2H), 7.38-7.35 (d, J=8.10 Hz, 1H), 7.31-7.19 (m,1H), 5.60-5.36 (m, 1H), 4.50-4.32 (m, 1H), 4.22-3.90 (m, 3H), 3.85-3.70(m, 1H), 3.66-3.59 (m, 2H), 3.24-3.22 (d, J=7.14 Hz, 1H), 2.53-2.42 (m,2H), 2.10-1.77 (m, 1H), 1.30 (s, 1H), 0.88-0.83 (m, 1H), 0.55-0.53 (m,1H). mGluR5 PAM EC₅₀: +.

Example 8.12 Synthesis of3-allyl-8-((3-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 8.2a. MS (ESI): 374(MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.25-8.22 (d, J=8.25 Hz, 1H), 7.77 (s, 1H), 7.62-7.56 (dd,J=8.26, 1.55 Hz, 1H), 7.41-7.35 (m, 2H), 7.28-7.27 (m, 1H), 7.16-7.07(m, 1H), 6.04-5.88 (m, 1H), 5.34-5.24 (m, 2H), 4.72-4.46 (m, 2H),3.42-3.12 (m, 4H), 3.05-2.65 (m, 4H). mGluR5 PAM EC₅₀: ++++. Fold shiftat 10 μM: ++.

Example 8.13 Synthesis of8-((3-fluorophenyl)ethynyl)-3-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-oneacetonitrile

A solution of8-((3-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one(100 mg, 0.3 mmol) and tetrahydrofuran-3-yl-benzenesulfonate (137 mg,0.6 mmol) in acetonitrile (20 mL) was stirred at room temperatureovernight. The mixture was diluted with H₂O (50 mL) and extracted withethyl acetate (3×50 mL), the combined organic layers were washed withbrine, dried over Na₂SO₄. After filtration and concentration, theresidue was purified by silica gel chromatography to give the desiredproduct. MS (ESI): 404(MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.25-8.22 (d,J=8.25 Hz, 1H), 7.77 (s, 1H), 7.58-7.55 (dd, J=8.25, 1.38 Hz, 1H),7.40-7.34 (m, 2H), 7.28-7.26 (m, 1H), 7.13-7.06 (m, 1H), 4.61-4.32 (m,2H), 4.02-3.95 (m, 1H), 3.90-3.70 (m, 3H), 3.25-3.22 (m, 3H), 2.89-2.74(m, 4H), 2.09-1.86 (m, 2H). mGluR5 PAM EC₅₀: ++.)

Example 8.14 Synthesis of the HCl salt of2-(8-((3-fluorophenyl)ethynyl)-11-oxo-1,2,4,5-tetrahyrdro-[1,4]diazepino[7,1-b]quinazolin-3(11H)-yl)acetonitrile

The title compound was prepared according to the experimental procedureas described in Example 8.2a. The product was then converted to thecorresponding HCl salt. MS (ESI): 373 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ8.18-8.15 (d, J=8.25 Hz, 1H), 7.82 (s, 1H), 7.70-7.66 (dd, J=8.24, 1.52Hz, 1H), 7.53-7.41 (m, 3H), 7.37-7.31 (m, 1H), 4.51-4.49 (m, 2H), 3.97(s, 2H), 3.34-3.31 (m, 2H), 2.51-2.49 (m, 4H). mGluR5 PAM EC₅₀: ++++.Fold shift at 10 μM: +++.

Example 8.15 Synthesis of2-(8-((3-fluorophenyl)ethynyl)-11-oxo-1,2,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-3(11H)-yl)-N-methylacetamide

The title compound was prepared according to the experimental procedureas described in Example 8.2a. DMF was used as the solvent. MS (ESI): 405(MH⁺); ¹H NMR (300 MHz, DMSO-d⁶+D₂O) δ 8.17-8.14 (d, J=8.16 Hz, 1H),7.78 (s, 1H), 7.69-7.65 (dd, J=8.21, 1.54 Hz, 1H), 7.54-7.45 (m, 3H),7.38-7.27 (m, 1H), 4.83-4.42 (s, 2H), 3.92 (s, 2H), 3.69-3.50 (m, 4H),3.50-3.45 (m, 2H), 2.68 (s, 3H). mGluR5 PAM EC₅₀: ++. Fold shift at 10μM: ++.

Example 8.16 Synthesis of8-((3-fluorophenyl)ethynyl)-3-((tetrahydrofuran-2-yl)methyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 8.2a. DMF was used as the solvent. MS (ESI): 418(MH⁺); ¹H NMR (300 MHz, DMSO-d⁶+D₂O) δ 8.17-8.14 (d, J=8.16 Hz, 1H),7.78 (s, 1H), 7.69-7.66 (d, J=8.19 Hz, 1H), 7.58-7.47 (m, 3H), 7.34-7.28(m, 1H), 5.22-4.97 (s, 1H), 4.30-4.12 (m, 2H), 3.93-3.73 (m, 4H),3.52-3.12 (m, 6H), 2.08-2.02 (m, 2H), 1.89-1.82 (m, 2H), 1.54-1.48 (m,1H). mGluR5 PAM EC₅₀: ++.

Example 8.17 Synthesis of3-acetyl-8-((3-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 8.20. MS (ESI): 376 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.27-8.23 (dd, J=8.36, 3.83 Hz, 1H), 7.89 (s, 1H), 7.62-7.58(dd, J=8.25, 1.50 Hz, 1H), 7.38-7.30 (m, 2H), 7.29-7.28 (m, 1H),7.14-7.08 (m, 1H), 4.56-4.48 (m, 2H), 4.00-3.92 (m, 2H), 3.84-3.75 (m,2H), 3.28-3.19 (m, 2H), 2.25-2.23 (d, J=7.83 Hz, 3H). mGluR5 PAM EC₅₀:++. Fold shift at 10 μM: +++.

Example 8.18 Synthesis of8-((3-fluorophenyl)ethynyl)-11-oxo-1,2,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazoline-3(11H)-carbaldehyde

A solution of8-((3-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one(0.1 g, 0.3 mmol), methyl formate (22 mg, 1.2 mmol), and2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (2.1 mg, 0.015 mmol)in toluene (3 mL) was stirred at room temperature for 12 h. The reactionmixture was quenched with saturated potassium bisulfate (5 mL). Thesolution was extracted with ethyl acetate (3×20 mL) and the combinedorganic layers were washed with brine, dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by silica gelchromatography to give the desired product. MS (ESI): 362 (M+H⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.27-8.23 (m, 1H), 8.20-8.18 (d, J=6.24 Hz, 1H),7.79-7.78 (m, 1H), 7.62-7.59 (m, 1H), 7.38-7.32 (m, 2H), 7.29-7.26 (m,1H), 7.14-7.07 (m, 1H), 4.57-4.49 (m, 2H), 3.94-3.84 (m, 2H), 3.75-3.65(m, 2H), 3.28-3.19 (m, 2H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM:++.

Example 8.19 Synthesis of the HCl salt of11-oxo-8-(pyridin-2-ylethynyl)-1,2,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazoline-3(11H)-carbaldehyde

The title compound was prepared according to the experimental procedureas described in Example 8.18. The product was then converted to thecorresponding HCl salt. MS (ESI): 345 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.76-8.74 (d, J=7.20 Hz, 1H), 8.46-8.42 (m, 1H), 8.42-8.28 (d, J=8.41Hz, 1H), 8.18-8.05 (m, 2H), 7.98-7.85 (m, 2H), 7.82-7.75 (m, 1H),4.61-4.45 (m, 2H), 3.90-3.67 (m, 4H), 3.52-3.24 (m, 2H).

Example 8.20 Synthesis of the HCl salt of3-acetyl-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

To a solution of8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one(120 mg, 0.38 mmol) and Na₂CO₃ (200 mg, 1.89 mmol) in acetone (20 mL)was added acetyl chloride (0.8 mL) dropwise. After stirring for 2 h, thereaction mixture was concentrated and diluted with water. The aqueousmixture was extracted with EtOAc (3×50 mL). The combined organic layerswere concentrated and purified by column chromatography to give 70 mg ofthe desired product. MS (ESI): 359 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.92-8.90 (d, J=5.64 Hz, 1H), 8.63-8.58 (m, 1H), 8.43-8.39 (dd, J=8.27Hz, 3.02 Hz, 1H), 8.31-8.28 (d, J=8.01 Hz, 1H), 8.08-8.01 (m, 2H),7.97-7.93 (m, 1H), 4.75 (d, 1H), 4.65 (d, 1H), 4.07-3.91 (m, 4H),3.56-3.53 (m, 1H), 3.46-3.42 (m, 1H), 2.2 (d, J=9.6 Hz, 3H).

Example 8.21 Synthesis of the 2HCl salt of8-(pyridin-2-ylethynyl)-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

To a solution of8-(2-(pyridin-2-yl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one(150 mg, 0.48 mmol), 3,3,3-trifluoropropanal (80 mg, 0.72 mmol), andsodium cyanoborohydride (60 mg, 0.96 mmol) in MeOH (10 mL) was addedacetic acid (29 mg, 0.48 mmol). The mixture was stirred for 1h at roomtemperature. The reaction mixture was quenched with saturated sodiumcarbonate solution (30 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine, dried over Na₂SO₄.After filtration and concentration, the crude product was purified bycolumn chromatography to give the desired product. The product was thenconverted to the corresponding 2HCl salt. MS (ESI): 413 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.94-8.92 (d, J=5.82 Hz, 1H), 8.72-8.66 (t, J=7.98Hz, 1H), 8.39-8.34 (t, J=9.00 Hz, 2H), 8.15-8.10 (t, J=7.83 Hz, 1H),8.07 (s, 1H), 7.91-7.88 (d, J=8.22 Hz, 1H), 4.84-4.80 (m, 3H), 3.81-3.71(m, 5H), 3.66-3.54 (m, 2H), 3.03-2.94 (m, 2H). mGluR5 PAM EC₅₀: ++. Foldshift at 10 μM: +++.

Example 8.22 Synthesis of the HCl salt of3-(prop-2-yn-1-yl)-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.29b. The product was then converted to thecorresponding HCl salt. MS (ESI): 355 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.70-8.66 (dd, J=5.88, 0.75 Hz, 1H), 8.72-8.66 (t, J=7.98 Hz, 1H),8.40-8.34 (t, J=8.60 Hz, 2H), 8.15-8.10 (m, 1H), 8.08-8.07 (d, J=1.08Hz, 1H), 7.92-7.89 (dd, J=8.27 Hz, 1.46 Hz, 1H), 4.83-4.81 (m, 2H),4.28-4.27 (d, J=2.40 Hz, 2H), 3.86-3.70 (m, 6H), 3.48-3.46 (t, J=2.46Hz, 1H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++.

Example 8.23 Synthesis of the 2HCl salt of2-(11-oxo-8-(pyridin-2-ylethynyl)-1,2,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-3(11H)-yl)acetonitrile

The title compound was prepared according to the experimental procedureas described in Example 2.29. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 356 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.85-8.83 (d, J=8.84 Hz, 1H), 8.61-8.55 (t, J=7.95 Hz, 1H), 8.39-8.33(d, J=8.28 Hz, 1H), 8.29-8.24 (d, J=8.10 Hz, 1H), 8.09-7.96 (m, 2H),7.93-7.89 (dd, J=8.28, 1.32 Hz, 1H), 4.64-4.62 (m, 2H), 3.89 (s, 2H),3.53-3.49 (m, 2H), 3.16-3.12 (m, 2H), 3.06-3.03 (m, 2H). mGluR5 PAMEC₅₀: +++. Fold shift at 10 μM: +++.

Example 8.24 Synthesis of the 2HCl salt of2-(11-oxo-8-(pyridin-2-ylethynyl)-1,2,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-3(11H)-yl)propanenitrile

The title compound was prepared according to the experimental procedureas described in Example 2.29. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 370 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.95-8.93 (d, J=5.70 Hz, 1H), 8.70-8.65 (t, J=8.00 Hz, 1H), 8.46-8.43(d, J=8.25 Hz, 1H), 8.36-8.34 (d, J=8.01 Hz, 1H), 8.16-8.06 (m, 2H),8.03-8.00 (d, J=8.01 Hz, 1H), 4.96-4.68 (m, 2H), 4.19-4.14 (m, 1H),3.66-3.52 (m, 2H), 3.28-2.94 (m, 4H), 1.58-1.56 (d, J=7.17 Hz, 3H).mGluR5 PAM EC₅₀: +.

Example 8.25 Synthesis of11)-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,3]diazepino[2,1-b]quinazolin-7(1H)-one

Example 8.25a Synthesis of (E)-methyl4-bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzoate

A solution of methyl 2-amino-4-bromobenzoate (1.0 g, 4.34 mmol, 1 eq)and 4,5-dichloro-1,2,3-dithiazolium chloride (2.0 g, 9.6 mmol, 2.2 eq)in DCM (20 mL) was stirred at rt under N₂ for 5 days. The reactionmixture was quenched with water and filtered. The filtrate was extractedwith ethyl acetate (3×100 mL). The combined organic layers were driedover Na₂SO₄. After filtration and concentration, the residue waspurified by silica gel chromatography to give the desired product. MS(ESI): 365, 367 (MH⁺).

Example 8.25b Synthesis of10-bromo-2,3,4,5-tetrahydro-[1,3]diazepino[2,1-b]quinazolin-7(1H)-one

To a stirred solution of (E)-methyl4-bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzoate (100 mg,0.27 mmol, 1 eq) in THF was added butane-1,4-diamine (0.027 mL, 0.27mmol, 1 eq) dropwise under N₂ and the reaction was heated at reflux for3 hours. After it was cooled to rt, the reaction mixture was dilutedwith water (20 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure to give the desired product, which was purified bysilica gel chromatography. MS (ESI): 294, 296 (MH⁺).

Example 8.25c Synthesis of10-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,3]diazepino[2,1-b]quinazolin-7(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 317 (MH⁺); ¹H NMR (300 MHz,CD₃OD) δ 8.94-8.92 (d, J=5.73 Hz, 1H), 8.69-8.64 (t, J=7.98 Hz, 1H),8.34-8.31 (d, J=8.07 Hz, 1H), 8.28-8.25 (d, J=8.19 Hz, 1H), 8.13-8.09(t, J=6.9 Hz, 1H), 7.81 (s, 1H), 7.76-7.73 (dd, J=8.21, 1.19 Hz, 1H),4.47-4.43 (t, J=6.3 Hz, 2H), 3.81-3.78 (t, J=3.9 Hz, 2H), 2.19-2.10 (m,4H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: ++.

Example 8.26 Synthesis of10-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,3]diazepino[2,1-b]quinazolin-7(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 343 (MH⁺); ¹HNMR (300 MHz, CD₃OD) δ 8.91-8.90 (d, J=5.4 Hz, 1H), 8.67-8.61 (t, J=7.9Hz, 1H), 8.38-8.35 (d, 8.10 Hz, 1H), 8.32-8.29 (d, J=8.10 Hz, 1H),8.10-8.06 (t, J=6.68 Hz, 1H), 8.02 (s, 1H), 7.86-7.83 (d, J=8.07 Hz,1H), 5.86 (broad, 1H), 4.97 (s, 2H), 3.77-3.58 (m, 4H), 2.59-2.38 (m,4H). mGluR5 PAM EC₅₀: ++.

Example 8.27 Synthesis of4-methyl-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

Example 8.27a Synthesis of (E)-(9H-fluoren-9-yl)methyl4-(hydroxyimino)-2-methylpiperidine-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 5.1a and Example 4.11a.

Example 8.27b Synthesis of (9H-fluoren-9-yl)methyl7-methyl-5-oxo-1,4-diazepane-1-carboxylate and (9H-fluoren-9-yl)methyl2-methyl-5-oxo-1,4-diazepane-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 4.11b. The two intermediates were separated inthis step.

Example 8.27c Synthesis of (9H-fluoren-9-yl)methyl8-bromo-4-methyl-11-oxo-1,2,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazoline-3(11H)-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 2.2a, Example 3.17b, and Example 1.1. MS (ESI):331 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ 10.00 (broad, 1H), 9.85 (broad,1H), 8.71-8.69 (d, J=4.2 Hz, 1H), 8.21-8.18 (d, J=8.25 Hz, 1H),8.05-8.00 (t, J=7.8 Hz, 1H), 7.86-7.83 (m, 2H), 7.75-7.73 (d, J=7.80 Hz,1H), 7.60-7.56 (t, J=4.8 Hz, 1H), 4.97-4.78 (m, 1H), 4.42-4.34 (m, 1H),3.68-3.56 (m, 3H), 3.31-3.21 (m, 2H), 1.41-1.39 (d, J=4.8 Hz, 3H).

Example 8.28 Synthesis of3,4-dimethyl-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.2a and Example 1.1. MS (ESI): 345 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.66 (m, 1H), 8.25-8.22 (d, J=8.25 Hz, 1H), 7.85(s, 1H), 7.79-7.70 (m, 1H), 7.64-7.57 (m, 2H), 7.32-7.57 (m, 1H),4.64-4.57 (m, 1H), 4.42-4.35 (m, 1H), 3.34-3.29 (d, J=14.08 Hz, 1H),3.18-3.10 (m, 1H), 3.07-2.94 (m, 2H), 2.76-2.65 (m, 1H), 2.43 (s, 3H),1.12-1.09 (d, J=6.39 Hz, 3H). mGluR5 PAM EC₅₀: +.

Example 8.29 Synthesis of the 2HCl salt of2-methyl-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a, Example 3.17b, and Example 1.1. Theproduct was then converted to the corresponding 2HCl salt. MS (ESI): 331(MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ 9.88-9.81 (m, 2H), 8.69-8.68 (d,J=4.71 Hz, 1H), 8.19-8.17 (d, J=8.22 Hz, 1H), 8.01-7.95 (m, 1H), 7.86(s, 1H), 7.82-7.79 (d, J=7.74 Hz, 1H), 7.74-7.71 (dd, J=8.18, 1.40 Hz,1H), 7.56-7.52 (m, 1H), 4.74-4.68 (d, J=15.88 Hz, 1H), 4.44-4.41 (m,1H), 3.68-3.51 (m, 3H), 3.39-3.26 (m, 2H), 1.34-1.32 (d, J=6.75 Hz, 3H).

Example 8.30 Synthesis of2,3-dimethyl-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.2a and Example 1.1. MS (ESI): 345 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.68-8.66 (d, J=4.74 Hz, 1H), 8.28-8.23 (d,J=8.25 Hz, 1H), 7.84 (s, 1H), 7.77-7.71 (t, J=7.8 Hz, 1H), 7.65-7.58 (m,2H), 7.32-7.28 (m, 1H), 4.72-4.71 (broad, 1H), 4.30-4.26 (m, 1H),3.27-3.25 (m, 1H), 3.19-2.97 (m, 3H), 2.85 (broad, 1H), 2.45 (s, 3H),1.03-1.00 (d, J=6.54 Hz, 3H). mGluR5 PAM EC₅₀: ++.

Example 8.31 Synthesis of1-methyl-10-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,3]diazepino[2,1-b]quinazolin-7(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 5.26b, Example 1.1 and Example 5.27. MS (ESI):331 (MH⁺).

Example 8.32 Synthesis of the 2HCl salt of3-(tert-butyl)-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.11a, Example 4.11b, Example 2.2a, and Example1.1. The product was then converted to the corresponding 2HCl salt. MS(ESI): 373 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 9.00-8.94 (s, 1H), 8.70-8.65(t, J=7.5 Hz, 1H), 8.39-8.33 (m, 2H), 8.13-8.09 (t, J=6.6 Hz, 1H), 8.05(s, 1H), 7.90-7.87 (dd, J=8.2, 1.2 Hz, 1H), 5.60-5.52 (dd, J=16.9, 5.7Hz, 1H), 4.29-4.12 (m, 3H), 3.98-3.89 (m, 1H), 3.51-3.33 (m, 3H), 1.53(s, 9H).

Example 9.1 Synthesis of3-((3-fluorophenyl)ethynyl)-14-methyl-8,9,10,11-tetrahydro-6H-7,10-epiminoazocino[2,1-b]quinazolin-13(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 6.20a, Example 4.11a, Example 4.11b, Example2.2a, Example 1.1, Example 1.21c, and Example 1.21d. MS (ESI): 374(MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.32-8.30 (d, J=7.80 Hz, 1H), 7.92 (s,1H), 7.85-7.82 (m, 1H), 7.51-7.44 (m, 2H), 7.38-7.35 (d, J=7.80 Hz, 1H),7.25-7.20 (m, 1H), 5.68-5.64 (m, 1H), 4.52-4.43 (m, 1H), 4.27-4.21 (m,1H), 4.11-4.06 (m, 1H), 3.89-3.80 (m, 1H), 3.03 (s, 3H), 2.50-2.39 (m,2H), 2.03-2.00 (m, 1H), 1.41-1.25 (m, 1H), 1.22-1.16 (m, 1H). mGluR5 PAMEC₅₀: +.

Example 9.2 and Example 9.3 Synthesis of the HCl salt of3-(pyridin-2-ylethynyl)-9,10,11,12,12a,13-hexahydro-6H-pyrido[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-15(7H)-oneand HCl salt of12-(pyridin-2-ylethynyl)-3,4,6,7,15,15a-hexahydro-1H-pyrido[1′,2′:4,5][1,4]diazepino[7,1-b]quinazolin-9(2H)-one

Example 9.2a 1-(but-3-ynyl)piperidine

A solution of piperidine (2.9 g, 33.8 mmol), 4-bromobut-1-yne (5 g, 37.6mmol) and K₂CO₃ (3 g, 2.2 mmol) in CH₃CN was stirred at 80° C. for 2h.After it was cooled to room temperature, the solution was diluted withH₂O and extracted with ethyl acetate (3×200 mL). Then the combinedorganic layers were dried over Na₂SO₄ and concentrated to give 2 g ofthe crude product, which was directly used for the next step withoutfurther purification. MS (ESI): 138 (MH⁺).

Example 9.2b Synthesis of hexahydro-1H-quinolizin-2(6H)-one

m-CPBA (600 mg, 3.65 mmol) was added into a solution of1-(but-3-ynyl)piperidine (500 mg, 3.65 mmol and 4 Å MS (5×weight ofm-CPBA) in DCM under N₂ at 0° C. The N-oxide formation was monitored byTLC. After completion, Ph₃PAuNTf₂ (134 mg, 0.18 mmol) was added to thereaction at 0° C. Upon completion, the mixture was diluted with DCM andthe molecular sieves were filtered off. The filtrate was washed with 5%aqueous Na₂CO₃, dried over Na₂SO₄ and concentrated under vacuum. Theresidue was used for the next reaction without further purification. MS(ESI): 154 (MH⁺).

Example 9.2c Synthesis of hexahydro-1H-quinolizin-2(6H)-one oxime

The title compound was prepared according to the experimental procedureas described in Example 4.11a. MS (ESI): 169 (MH⁺).

Example 9.2d and Example 9.3d Synthesis ofoctahydropyrido[1,2-d][1,4]diazepin-2(1H)-one andoctahydropyrido[1,2-a][1,4]diazepin-3(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 4.11b. MS (ESI): 169 (MH⁺).

Example 9.2e and Example 9.3e Synthesis of3-bromo-9,10,11,12,12a,13-hexahydro-6H-pyrido[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-15(7H)-oneand12-bromo-3,4,6,7,15,15a-hexahydro-1H-pyrido[1′,2′:4,5][1,4]diazepino[7,1-b]quinazolin-9(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a. MS (ESI): 348-350 (MH⁺)

Example 9.2f and Example 9.3f Synthesis of the HCl salt of3-(pyridin-2-ylethynyl)-9,10,11,12,12a,13-hexahydro-6H-pyrido[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-15(7H)-oneand the HCl salt of12-(pyridin-2-ylethynyl)-3,4,6,7,15,15a-hexahydro-1H-pyrido[1′,2′:4,5][1,4]diazepino[7,1-b]quinazolin-9(2H)-one

The title compounds were prepared according to the experimentalprocedure as described in Example 1.1. The products were then convertedto the corresponding HCl salt. MS (ESI): 371 (MH⁺);

3-(pyridin-2-ylethynyl)-9,10,11,12,12a,13-hexahydro-6H-pyrido[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-15(7H)-one

MS (ESI): 371 (MH⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.92-8.90 (d, J=5.82 Hz,1H), 8.68-8.63 (d, J=7.99 Hz, 1H), 8.37-8.30 (m, 2H), 8.11-8.07 (t,J=6.48 Hz, 1H), 8.03 (s, 1H), 7.87-7.84 (d, J=8.25 Hz, 1H), 5.21-5.15(d, J=16.78 Hz, 1H), 4.19-4.11 (m, 1H), 3.97-3.84 (m, 2H), 3.63-3.42 (m,3H), 3.09-3.06 (m, 1H), 2.27-2.20 (m, 1H), 2.15-3.39 (m, 1H), 2.03-1.89(m, 4H), 1.68-1.64 (m, 2H). mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM:+++.

12-(pyridin-2-ylethynyl)-3,4,6,7,15,15a-hexahydro-1H-pyrido[1′,2′:4,5][1,4]diazepino[7,1-b]quinazolin-9(2H)-one

MS (ESI): 371 (MH⁺); ¹H NMR (300 MHz, CD₃OD): δ 8.93-8.91 (d, J=5.85 Hz,1H), 8.70-8.64 (d, J=7.98 Hz, 1H), 8.38-8.32 (m, 2H), 8.13-8.08 (t,J=7.17 Hz, 1H), 8.03 (s, 1H), 7.88-7.85 (d, J=8.24 Hz, 1H), 5.54-5.57(m, 1H), 4.30-4.211 (m, 1H), 3.94-3.82 (m, 2H), 3.63-3.59 (m, 2H),3.47-3.39 (m, 1H), 3.20-3.15 (d, J=16.15 Hz, 1H), 3.10-3.00 (m, 1H),2.15-3.39 (m, 1H), 2.00-1.88 (m, 3H), 1.73-1.64 (m, 2H).

Example 9.4 and Example 9.5 Synthesis of the HCl salt of9-(pyridin-2-ylethynyl)-2,3,5,6,14,14a-hexahydropyrrolo[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-12(1H)-oneand the HCl salt of11-(pyridin-2-ylethynyl)-2,3,5,6,14,14a-hexahydropyrrolo[1′,2′:4,5][1,4]diazepino[7,1-b]quinazolin-8(1H)-one

The title compounds were prepared according to the experimentalprocedure as described in Example 9.2a, Example 9.2b, Example 4.11a,Example 4.11b, Example 2.2a, and Example 1.1. The products were thenconverted to the corresponding HCl salt.

9-(Pyridin-2-ylethynyl)-2,3,5,6,14,14a-hexahydropyrrolo[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-12(1H)-one

MS (ESI): 357 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.93-8.92 (d, J=3.00 Hz,1H), 8.72-8.66 (dt, J=7.97, 1.48 mHz, 1H), 8.40-8.34 (t, J=8.74 Hz, 2H),8.15-8.10 (dt, J=13.71, 1.02 Hz, 1H), 8.08 (s 1H), 7.93-7.90 (dd,J=8.25, 1.32 Hz, 1H), 5.64-5.58 (d, J=10.8 Hz, 1H), 4.24-4.16 (m, 1H),4.07-4.04 (m, 1H), 3.88-3.84 (m, 2H), 3.66-3.48 (m, 3H), 3.28-3.21 (m,1H), 2.52-2.49 (m, 1H), 2.29-2.21 (m, 3H). mGluR5 PAM EC₅₀: +++. Foldshift at 10 μM: +++.

11-(pyridin-2-ylethynyl)-2,3,5,6,14,14a-hexahydropyrrolo[1′,2′:4,5][1,4]diazepino[7,1-b]quinazolin-8(1H)-one

MS (ESI): 357 (M+H⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.91-8.91 (d, J=5.04 Hz,1H), 8.71-8.65 (dt, J=7.99, 1.53 Hz, 1H), 8.38-8.32 (m, 2H), 8.14-8.09(m, 1H), 8.05-8.04 (d, J=1.14 Hz, 1H), 7.89-7.86 (dd, J=8.20, 1.45 Hz,1H), 5.59-5.55 (m, 1H), 4.12-4.07 (m, 2H), 3.86-3.81 (m, 2H), 3.75-3.69(m, 1H), 3.51-3.45 (m, 2H), 3.28-3.19 (m, 1H), 2.59-2.50 (m, 1H),2.21-2.00 (m, 3H). mGluR5 PAM EC₅₀: ++.

Example 9.4a and Example 9.4b Separation of enantiomers of9-(pyridin-2-ylethynyl)-2,3,5,6,14,14a-hexahydropyrrolo[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-12(1H)-oneinto(S)-9-(pyridin-2-ylethynyl)-2,3,5,6,14,14a-hexahydropyrrolo[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-12(1H)-oneand(R)-9-(pyridin-2-ylethynyl)-2,3,5,6,14,14a-hexahydropyrrolo[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-12(1H)-one

Racemic9-(pyridin-2-ylethynyl)-2,3,5,6,14,14a-hexahydropyrrolo[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-12(1H)-onewas separated into the corresponding two single enantiomer compounds(S)-9-(pyridin-2-ylethynyl)-2,3,5,6,14,14a-hexahydropyrrolo[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-12(1H)-oneand(R)-9-(pyridin-2-ylethynyl)-2,3,5,6,14,14a-hexahydropyrrolo[2′,1′:3,4][1,4]diazepino[7,1-b]quinazolin-12(1H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 4.6×100 mm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was methanol:isopropanol)1:1) with 0.1%isopropylamine. Isocratic Method: 50% Co-solvent at 4 mL/min SystemPressure: 100 bar. Column Temperature 25° C.

Faster moving enantiomer (fraction 1): Retention time=1.8 min 99.6% ee.mGluR5 PAM EC₅₀: +++.Slower moving enantiomer (fraction 2): Retention time=2.5 min. 99.2% ee.mGluR5 PAM EC₅₀: ++.

Example 10.1 and Example 10.2 Synthesis of the HCl salt of11-((4-fluorophenyl)ethynyl)-3-methyl-3,4,5,6-tetrahydro-1H-[1,5]diazocino[2,1-b]quinazolin-8(2H)-oneand the HCl salt of9-((4-fluorophenyl)ethynyl)-3-methyl-3,4,5,6-tetrahydro-1H-[1,4]diazocino[8,1-b]quinazolin-12(2H)-one

Example 10.1a Synthesis of 1-tert-butyl 4-ethyl5-oxoazepane-1,4-dicarboxylate

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.2 g, 16mmol, 1.0 equiv) in Et₂O (20 mL) at −50° C. were added BF₃.Et₂O (2.3 g,16 mmol, 1.0 equiv) in dropwise. After completion of addition ofBF₃.Et₂O, ethyl 2-diazoacetate (2 g, 17.6 mmol, 1.1 equiv) was addeddropwise. The reaction was then stirred at −50° C. for an hour and keptat room temperature overnight. Then the reaction mixture was poured intowater (100 mL), extracted with ethyl acetate (3×100 mL), combined of theorganic layers and dried over Na₂SO₄. The solvent was removed underreduced pressure to give the desired product (4 g), which was purifiedby silica gel chromatography. MS (ESI): 286 (MH⁺).

Example 10.1b Synthesis of azepan-4-one hydrochloride

A solution of 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (0.9g, 3.16 mmol, 1 equiv) in aq. HCl (30 mL, 4N) was stirred at reflux for7 h. The reaction mixture was then concentrated to give the desiredproduct, which was directly used for the next step without furtherpurification. MS (ESI): 114 (MH⁺).

Example 10.1c Synthesis of (E,Z)-(9H-fluoren-9-yl)methyl4-(hydroxyimino)azepane-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 5.1a, Example 4.11a. MS (ESI): 351 (MH⁺).

Example 10.1d and Example 10.2d Synthesis of (9H-fluoren-9-yl)methyl4-oxo-1,5-diazocane-1-carboxylate and (9H-fluoren-9-yl)methyl5-oxo-1,4-diazocane-1-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 4.11b. MS (ESI): 351 (MH⁺).

Example 10.1e and Example 10.2e Synthesis of (9H-fluoren-9-yl)methyl9-bromo-12-oxo-4,5,6,12-tetrahydro-1H-[1,4]diazocino[8,1-b]quinazoline-3(2H)-carboxylateand (9H-fluoren-9-yl)methyl11-bromo-8-oxo-4,5,6,8-tetrahydro-1H-[1,5]diazocino[2,1-b]quinazoline-3(2H)-carboxylate

The title compounds were prepared according to the experimentalprocedure as described in Example 2.2a. MS (ESI): 530, 532 (MH⁺).

Example 10.1f and Example 10.2f Synthesis of9-bromo-3,4,5,6-tetrahydro-1H-[1,4]diazocino[8,1-b]quinazolin-12(2H)-one and11-bromo-3,4,5,6-tetrahydro-1H-[1,5]diazocino[2,1-b]quinazolin-8(2H)-one

The title compounds were prepared according to the experimentalprocedure as described in Example 3.17b. MS (ESI): 308, 310 (MH⁺).

Example 10.1g and Example 10.2g Synthesis of9-bromo-3-methyl-3,4,5,6-tetrahydro-1H-[1,4]diazocino[8,1-b]quinazolin-12(2H)-oneand11-bromo-3-methyl-3,4,5,6-tetrahydro-1H-[1,5]diazocino[2,1-b]quinazolin-8(2H)-one

The title compounds were prepared according to the experimentalprocedure as described in Example 5.2a. MS (ESI): 322, 324 (MH⁺).

Example 10.1h and Example 10.2h Synthesis of the HCl salt of11-((4-fluorophenyl)ethynyl)-3-methyl-3,4,5,6-tetrahydro-1H-[1,5]diazocino[2,1-b]quinazolin-8(2H)-oneand the HCl salt of9-((4-fluorophenyl)ethynyl)-3-methyl-3,4,5,6-tetrahydro-1H-[1,4]diazocino[8,1-b]quinazolin-12(2H)-one

The title compounds were prepared according to the experimentalprocedure as described in Example 1.1. The products were then convertedto the corresponding HCl salt. MS (ESI): 362 (MH⁺).

11-((4-fluorophenyl)ethynyl)-3-methyl-3,4,5,6-tetrahydro-1H-[1,5]diazocino[2,1-b]quinazolin-8(2H)-one

MS (ESI): 362 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.21 (d, J=8.25 Hz,1H), 7.77 (s, 1H), 7.72-7.52 (m, 3H), 7.12-7.05 (m, 2H), 4.42 (broad,2H), 3.05-3.00 (t, J=6.12 Hz, 2H), 2.80-2.78 (m, 2H), 2.63-2.60 (t,J=5.46 Hz, 2H), 2.34 (s, 3H), 2.06-2.00 (m, 2H). mGluR5 PAM EC₅₀: ++++.

9-((4-fluorophenyl)ethynyl)-3-methyl-3,4,5,6-tetrahydro-1H-[1,4]diazocino[8,1-b]quinazolin-12(2H)-one

MS (ESI): 362 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.21 (d, J=8.25 Hz,1H), 7.77 (s, 1H), 7.72-7.52 (m, 3H), 7.12-7.05 (m, 2H), 4.40 (broad,2H), 3.05-3.00 (t, J=6.12 Hz, 2H), 2.80-2.78 (m, 2H), 2.63-2.60 (t,J=5.46 Hz, 2H), 2.34 (s, 3H), 2.06-2.00 (m, 2H). mGluR5 PAM EC₅₀: +++.Fold shift at 10 μM: ++.

Example 10.3 and Example 10.4 Synthesis of the HCl salt of11-((3-fluorophenyl)ethynyl)-3-methyl-3,4,5,6-tetrahydro-1H-[1,5]diazocino[2,1-b]quinazolin-8(2H)-oneand the HCl salt of9-((3-fluorophenyl)ethynyl)-3-methyl-3,4,5,6-tetrahydro-1H-[1,4]diazocino[8,1-b]quinazolin-12(2H)-one

The title compounds were prepared according to the experimentalprocedure as described in Example 1.1. The products were then convertedto the corresponding HCl salt. MS (ESI): 362 (MH⁺).

11-((3-fluorophenyl)ethynyl)-3-methyl-3,4,5,6-tetrahydro-1H-[1,5]diazocino[2,1-b]quinazolin-8(2H)-one

¹H NMR (300 MHz, CDCl₃) δ 8.25-8.23 (d, J=7.80 Hz, 1H), 7.79 (s, 1H),7.57-7.54 (d, J=8.22 Hz, 1H), 7.38-7.35 (m, 2H), 7.26-7.25 (m, 1H),7.14-7.17 (m, 1H), 4.44-4.42 (m, 2H), 3.16-3.13 (m, 2H), 3.01-2.97 (m,2H), 2.47 (m, 2H), 2.45 (s, 3H), 1.94-1.87 (m, 2H). mGluR5 PAM EC₅₀:++++. Fold shift at 10 μM: ++.

9((3-fluorophenyl)ethynyl)-3-methyl-3,4,5,6-tetrahydro-1H-[1,4]diazocino[8,1-b]quinazolin-12(2H)-one

¹H NMR (300 MHz, CDCl₃) δ 8.25-8.22 (d, J=8.25 Hz, 1H), 7.79 (s, 1H),7.56-7.53 (d, J=8.30 Hz, 1H), 7.37-7.34 (m, 2H), 7.26-7.25 (m, 1H),7.13-7.06 (m, 1H), 4.42-4.32 (m, 2H), 3.03-3.00 (t, J=6.09 Hz, 2H), 2.80(s, 2H), 2.63-2.60 (t, J=5.16 Hz, 2H), 2.34 (s, 3H), 2.04-2.00 (m, 2H).mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.

Example 10.5 and Example 10.6 Synthesis of9-((3-fluorophenyl)ethynyl)-2,3,5,6-tetrahydro-1H-[1,4]diazocino[8,1-b]quinazoline-4,12-dioneand of11-((3-fluorophenyl)ethynyl)-2,3,5,6-tetrahydro-1H-[1,5]diazocino[2,1-b]quinazoline-4,8-dione

The title compounds were prepared according to the experimentalprocedure as described in Example 4.11a and Example 4.11b. MS (ESI): 362(MH⁺).

9-((3-fluorophenyl)ethynyl)-2,3,5,6-tetrahydro-1H-[1,4]diazocino[8,1-b]quinazoline-4,12-dione

¹H NMR (300 MHz, DMSO-d⁶) δ 8.15-8.12 (d, J=8.25 Hz, 1H), 7.77-7.76 (d,J=1.02 Hz, 1H), 7.69-7.63 (m, 2H), 7.53-7.46 (m, 3H), 7.36-7.33 (m, 1H),4.41 (m, 2H), 3.65 (m, 2H), 3.34 (m, 2H), 2.91-2.89 (m, 2H). mGluR5 PAMEC₅₀: +++.

11-((3-fluorophenyl)ethynyl)-2,3,5,6-tetrahydro-1H-[1,5]diazocino[2,1-b]quinazoline-4,8-dione

¹H NMR (300 MHz, CD₃OD) δ 8.22-8.20 (d, J=8.40 Hz, 1H), 7.76 (s, 1H),7.66-7.63 (dd, J=8.28, 1.5 Hz, 1H), 7.49-7.41 (m, 2H), 7.37-7.34 (m,1H), 7.23-7.16 (m, 1H), 4.63-4.58 (m, 2H), 3.66-3.62 (t, J=6.47 Hz, 2H),3.55 (m, 1H), 3.47-3.42 (m, 2H), 3.11-3.06 (m, 1H), 2.94-2.86 (t, J=7.41Hz, 1H). mGluR5 PAM EC₅₀: +++.

Example 11.1 Synthesis of the HCl salt of7-((3-fluorophenyl)ethynyl)-3-(2-methoxyethyl)pyrido[3,2-d]pyrimidin-4(3H)-one

Example 11.1a Synthesis of 7-bromopyrido[3,2-d]pyrimidin-4(3H)-one

A solution of 3-amino-5-bromopicolinic acid (1.0 g, 4.6 mmol) informamide (1.1 g, 25 mmol) was stirred at 150° C. for 4 h. After it wascooled to room temperature, the reaction mixture was poured into water(50 mL). A suspension was formed and filtered. The cake was washed withwater and dried to give the desired product. MS (ESI): 226, 228 (MH⁺).

Example 11.1b Synthesis of7-bromo-3-(2-methoxyethyl)pyrido[3,2-d]pyrimidin-4(3H)-one

A solution of 7-bromopyrido[3,2-d]pyrimidin-4(3H)-one (200 mg, 0.89mmol), 1-bromo-2-methoxyethane (148 mg, 1.06 mmol) and K₂CO₃ (184 mg,1.3 mmol) in acetone (10 mL) and DMF (3 mL) was stirred at roomtemperature for 4 h. Then the mixture was diluted with H₂O (50 mL) andextracted with ethyl acetate (3×50 mL), the combined organic layers werewashed with brine, dried over Na₂SO₄. After filtration andconcentration, the residue was purified by silica gel chromatography togive the desired product. MS (ESI): 284, 286 (MH⁺).

Example 11.1c Synthesis of HCl salt of7-((3-fluorophenyl)ethynyl)-3-(2-methoxyethyl)pyrido[3,2-d]pyrimidin-4(3H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 324 (MH⁺). MS (ESI): 324 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 8.61 (m, 1H), 8.37 (s, 1H), 7.50-7.40 (m, 3H),7.28-7.21 (m, 1H), 4.35-4.32 (t, J=9.57 Hz, 2H), 3.76-3.73 (t, J=9.21Hz, 2H), 3.37 (s, 3H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++.

Example 11.2 Synthesis of2-(1-methoxyethyl)-3-methyl-7-(pyridin-2-ylethynyl)pyrido[3,2-d]pyrimidin-4(3H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.1a, Example 2.1b, Example 2.1c, and Example1.1. MS (ESI): 321 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 9.01 (s, 1H),8.71-8.69 (m, 1H), 8.22-8.21 (d, J=1.5 Hz, 1H), 7.80-7.74 (dt, J=7.80,1.8 Hz, 1H), 7.65-7.62 (d, J=7.8 Hz, 1H), 7.37-7.32 (m, 1H), 4.68-4.64(q, J=6.6 Hz, 1H), 3.82 (s, 3H), 3.43 (s, 3H), 1.67-1.65 (d, J=6.6 Hz,3H).

Example 11.3 Synthesis of the 2HCl salt of8-(hydroxymethyl)-3-(pyridin-2-ylethynyl)-7,8-dihydropyrido[3,2-d]pyrrolo[1,2-a]pyrimidin-10(6H)-one

Example 11.3a Synthesis of (9H-fluoren-9-yl)methyl(5-oxopyrrolidin-2-yl)methyl carbonate

To a solution of 5-(hydroxymethyl)pyrrolidin-2-one (3 g, 26 mmol) in DCM(150 mL) was added Fmoc-Cl (8.1 g, 31 mmol) and pyridine (2 mL). Themixture was stirred for 2 h at room temperature. Then the reactionmixture was diluted with water (150 mL) and extracted with DCM (3×150mL). The combined organic layers were washed with brine, dried overNa₂SO₄. After filtration and concentration, the crude product waspurified by column chromatography to give 4.2 g of the desired product.MS (ESI): 338 (MH⁺).

Example 11.3b Synthesis of (9H-fluoren-9-yl)methyl(3-bromo-10-oxo-6,7,8,10-tetrahydropyrido[3,2-d]pyrrolo[1,2-a]pyrimidin-8-yl)methylcarbonate

To a solution of (9H-fluoren-9-yl)methyl (5-oxopyrrolidin-2-yl)methylcarbonate (1.2 g, 3.57 mmol) and 3-amino-5-bromopicolinic acid (0.77 g,3.57 mmol) in 1,4-dioxane (50 mL) was added POCl₃ (6 mL). The mixturewas stirred for 2 h at 85° C. After the reaction mixture was cooled toroom temperature, it was diluted with saturated sodium carbonatesolution (200 mL) and extracted with EtOAc (3×200 mL). The combinedorganic layers were washed with brine and dried over Na₂SO₄. Afterfiltration and concentration, the crude product was purified by columnchromatography to give 1.4 g of the desired product. MS (ESI): 518(MH⁺).

Example 11.3c Synthesis of8-(hydroxymethyl)-3-bromo-7,8-dihydropyrido[3,2-d]pyrrolo[1,2-a]pyrimidin-10(6H)-one

To a solution of (9H-fluoren-9-yl)methyl(3-bromo-10-oxo-6,7,8,10-tetrahydropyrido[3,2-d]pyrrolo[1,2-a]pyrimidin-8-yl)methylcarbonate (1.4 g, 4.7 mmol) in DCM (50 mL) was added Et₃N (4 mL). Themixture was stirred for 5 h at room temperature. The reaction mixturewas then concentrated and purified by column chromatography to give 0.6g of the desired product. MS (ESI): 296, 298 (MH⁺).

Example 11.3d Synthesis of the 2HCl salt of8-(hydroxymethyl)-3-(pyridin-2-ylethynyl)-7,8-dihydropyrido[3,2-d]pyrrolo[1,2-a]pyrimidin-10(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 319 (MH⁺); ¹H NMR (300 MHz, D₂O) δ8.86 (s, 1H), 8.74-8.72 (d, J=5.82 Hz, 1H), 8.53-8.47 (t, J=8.00 Hz,1H), 8.28 (s, 1H), 8.15-8.13 (d, J=8.10 Hz, 1H), 7.98-7.94 (m, 1H),4.85-4.39 (m, 1H), 4.10-4.04 (dd, J=12.20, 3.77 Hz, 1H), 3.84-3.79 (dd,J=12.24 Hz, 2.61 Hz, 1H), 3.36-3.27 (m, 1H), 3.11-3.02 (m, 1H),2.50-2.43 (m, 1H), 2.29-2.21 (m, 1H). mGluR5 PAM EC₅₀: +.

Example 11.4 Synthesis of 2HCl salt of3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-dipyrido[1,2-a:3′,2′-d]pyrimidin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. The product was thenconverted to the corresponding 2HCl salt. MS (ESI): 303 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 9.02 (s, 1H), 8.82-8.80 (d, J=4.80 Hz, 1H), 8.42-8.36(m, 2H), 8.14-8.12 (d, J=7.92 Hz, 1H), 7.92-7.87 (t, J=7.74 Hz, 1H),4.18-4.14 (m, 2H), 3.20-3.15 (m, 2H), 2.15-1.98 (m, 4H).

Example 11.5 Synthesis of the 2HCl salt of8,8-dimethyl-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-dipyrido[1,2-a:3′,2′-d]pyrimidin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 11.7a, Example 11.7b, and Example 1.1. Theproduct was then converted to the corresponding 2HCl salt. MS (ESI):331(MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 9.15 (s, 1H), 8.98-8.96 (dd, J=5.72,0.735 Hz, 1H), 8.69-8.64 (dt, J=7.98, 1.49 Hz, 1H), 8.53-8.52 (d, J=1.53Hz, 1H), 8.38-8.36 (d, J=7.98 Hz, 1H), 8.15-8.10 (m, 1H), 3.94 (s, 2H),3.37-3.31 (t, J=6.8 Hz, 2H), 1.91-1.86 (t, J=6.8 Hz, 2H), 1.20 (s, 6H).mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM: ++.

Example 11.6 Synthesis of3-(pyridin-2-ylethynyl)-9,10,10a,11-tetrahydro-6H-pyrido[3,2-d]pyrrolo[1′,2′:4,5]pyrazino[1,2-a]pyrimidin-13(8H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 344 (MH⁺); ¹HNMR (300 MHz, CD₃OD) δ 9.09 (s, 1H), 8.96-8.94 (d, J=5.13 Hz, 1H),8.699-8.64 (m, 1H), 8.54-8.53 (d, J=1.62 Hz, 1H), 8.37-8.34 (d, J=7.92Hz, 1H), 8.14-8.10 (m, 1H), 4.95-4.89 (m, 2H), 4.80-4.75 (m, 1H),4.64-4.59 (m, 1H), 4.38-4.34 (m, 2H), 3.91 (m, 1H), 2.49-2.47 (m, 1H),2.26-2.22 (m, 1H), 2.04-1.97 (m, 2H). mGluR5 PAM EC₅₀: +.

Example 11.7 Synthesis of the HCl salt of3-((3-fluorophenyl)ethynyl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-one

Example 11.7a Synthesis of (E)-7-methoxy-3,4,5,6-tetrahydro-2H-azepine

A solution of azepan-2-one (5.0 g, 44 mmol) and trimethyloxoniumtetrafluoroborate (7.8 g, 53 mmol) in DCM (30 mL) was stirred at roomtemperature for 12 h. Then the reaction mixture was quenched withsaturated sodium carbonate (50 mL) and extracted with DCM (3×100 mL).The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated to give the desired product. MS (ESI): 128 (MH⁺).

Example 11.7b Synthesis of3-bromo-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-one

A solution of 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (1.0 g, 8.8 mmol)and 3-amino-5-bromopicolinic acid (1.9 g, 8.8 mmol) in DMF (70 mL) wasstirred at 130° C. for 48 h. The reaction mixture was diluted with H₂O(300 mL) and extracted with DCM (3×300 mL). The combined organic layerswere washed with saturated sodium carbonate and brine, dried overNa₂SO₄. After filtration and concentration, the residue was purified bysilica gel chromatography to give the desired product. MS (ESI): 294,296 (MH⁺).

Example 11.7c Synthesis of HCl salt of3-bromo-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding HCl salt. MS (ESI): 334 (MH⁺). MS (ESI): 334(MH⁺); ¹H NMR(300 MHz, DMSO-d⁶) δ 8.89 (s, 1H), 8.20 (s, 1H), 7.56-7.51 (m, 3H),7.40-7.33 (m, 1H), 4.37-4.35 (m, 2H), 3.12 (s, 2H), 1.77 (s, 6H). mGluR5PAM EC₅₀: +++++. Fold shift at 10 μM: +.

Example 11.8 Synthesis of the 2HCl salt of3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. The product was then converted to thecorresponding 2HCl salt. MS (ESI): 317 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ9.16 (s, 1H), 8.99-8.97 (d, J=5.07 Hz, 1H), 8.72-8.66 (m, 1H), 8.57 (s,1H), 8.40-8.38 (d, J=8.01 Hz, 1H), 8.17-8.12 (m, 1H), 4.60-4.57 (m, 2H),3.41-3.38 (m, 2H), 2.03-1.92 (m, 6H). mGluR5 PAM EC₅₀: ++.

Example 11.9 Synthesis of the 2HCl salt of8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 11.7a, Example 11.7b, and Example 1.1. Theproduct was then converted to the corresponding 2HCl salt. MS (ESI): 331(MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ 8.96-8.95 (d, J=1.89 Hz, 1H),8.71-8.69 (d, J=4.89 Hz, 1H), 8.32-8.31 (d, J=1.92 Hz, 1H), 8.02-7.97(t, J=7.62 Hz, 1H), 7.85-7.83 (d, J=7.80 Hz, 1H), 7.58-7.54 (t, J=7.62Hz, 1H), 4.95-4.88 (m, 1H), 3.84-3.75 (m, 1H), 3.29-3.20 (m, 1H),3.10-3.03 (m, 1H), 2.02-1.88 (m, 3H), 1.39-1.16 (m, 2H), 0.93-0.91 (d,J=6.42 Hz, 3H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM: +++.

Example 11.9a and Example 11.9b Separation of enantiomers of8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-oneinto(S)-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-oneand(R)-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-one

Racemic8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-onewas separated into the corresponding two single enantiomer compounds(S)-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-oneand(R)-8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-oneusing chiral chromatography with an isocratic SFC method. The columnused was a 4.6×100 mm RegisPack from Regis Technologies (Morton Grove,Ill.). The CO₂ co-solvent was isopropanol with 0.1% isopropylamine.Isocratic Method: 50% Co-solvent at 4 mL/min System Pressure: 100 bar.Column Temperature 25° C.

Faster moving enantiomer of8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-one (fraction 1): Retention time=3.3min 100% ee. mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.Slower moving enantiomer of8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrimido[1,2-a]azepin-12(6H)-one(fraction 2): Retention time=3.9 min 99.7% ee. mGluR5 PAM EC₅₀: ++++.Fold shift at 10 μM: +++.

Example 11.10 Synthesis of7,7-dimethyl-3-(pyridin-2-ylethynyl)-7,8-dihydropyrido[3,2-d]pyrrolo[1,2-a]pyrimidin-10(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 317 (MH⁺); ¹HNMR (300 MHz, CD₃OD) δ 9.05 (broad, 1H), 8.98-8.96 (d, J=5.46 Hz, 1H),8.72-8.70 (t, J=7.97 Hz, 1H), 8.67 (s, 1H), 8.46-8.39 (d, J=7.95 Hz,1H), 8.16-8.12 (t, J=6.9 Hz, 1H), 4.06 (s, 2H), 3.15 (s, 2H), 1.34 (s,6H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++.

Example 11.12 Synthesis of8-(methoxymethyl)-3-(pyridin-2-ylethynyl)-7,8-dihydropyrido[3,2-d]pyrrolo[1,2-a]pyrimidin-10(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a, Example 3.17b, Example 4.25, and Example1.1. MS (ESI): 333 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.97 (s, 1H),8.70-8.68 (d, J=1.80 Hz, 1H), 8.16 (s, 1H), 7.79-7.71 (m, 1H), 7.66-7.63(d, J=7.80 Hz, 1H), 7.37-7.28 (m, 1H), 5.00-4.96 (m, 1H), 4.09-4.04 (dd,J=9.96, 3.27 Hz, 1H), 3.67-3.63 (dd, J=9.96, 2.34 Hz, 1H), 3.50-3.37 (m,1H), 3.31 (s, 3H), 3.08-2.98 (m, 1H), 2.47-2.23 (m, 2H).

Example 11.13 Synthesis of the 2HCl salt of7-methyl-3-(pyridin-2-ylethynyl)-7,8-dihydropyrido[3,2-d]pyrrolo[1,2-a]pyrimidin-10(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. The product was thenconverted to the corresponding 2HCl salt. MS (ESI): 303 (MH⁺); ¹H NMR(300 MHz, CD₃OD) δ 9.07 (s, 1H), 8.98-8.96 (d, J=5.6 Hz, 1H), 8.72-8.67(t, J=8.0 Hz, 1H), 8.47 (s, 1H), 8.39-8.37 (d, J=8.0 Hz, 1H), 8.16-8.12(t, J=6.8 Hz, 1H), 4.52-4.45 (dd, J=12.3, 7.8 Hz, 1H), 3.90-3.84 (dd,J=12.3, 7.2 Hz, 1H), 3.52-3.44 (dd, J=17.4, 7.8 Hz, 1H), 3.07-3.00 (dd,J=17.4, 7.5 Hz, 1H), 2.98-2.86 (m, 1H), 1.33-1.30 (d, J=6.7 Hz, 3H).mGluR5 PAM EC₅₀: +.

Example 12.1 Synthesis of2-(1-methoxyethyl)-3-methyl-7-(pyridin-2-ylethynyl)pyrido[2,3-d]pyrimidin-4(3H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.1a, Example 2.1b, Example 2.1c, and Example1.1. MS (ESI): 321 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.69-8.64 (m, 2H),7.98-7.92 (m, 1H), 7.85-7.80 (m, 2H), 7.55-7.50 (m, 1H), 4.82-4.80 (q,J=6.57 Hz, 1H), 3.75 (s, 3H), 3.45 (s, 3H), 1.67-1.65 (d, J=6.57 Hz,3H).

Example 12.2 and Example 12.3 Synthesis of9,9-dimethyl-2-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:2′,3′-d]pyrimidin-5-oneand8,8-dimethyl-2-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:2′,3′-d]pyrimidin-5-one

Example 12.2a and Example 12.3a Synthesis of9,9-dimethyl-2-chloro-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:2′,3′-d]pyrimidin-5-oneand8,8-dimethyl-2-chloro-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:2′,3′-d]pyrimidin-5-one

The title compounds were prepared according to the experimentalprocedure as described in Example 2.2a.

Example 12.2b and Example 12.3b Synthesis of9,9-dimethyl-2-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:2′,3′-d]pyrimidin-5-oneand8,8-dimethyl-2-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:2′,3′-d]pyrimidin-5-one

The title compounds were prepared according to the experimentalprocedure as described in Example 1.1.

9,9-dimethyl-2-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:2′,3′-d]pyrimidin-5-one

MS (ESI): 331 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.68-8.67 (d, J=3.63 Hz,1H), 8.60-8.57 (d, J=7.98 Hz, 1H), 7.77-7.64 (m, 3H), 7.35-7.28 (m, 1H),4.11-4.01 (t, J=6.45 Hz, 2H), 2.88 (m, 2H), 1.89-1.84 (m, 2H), 1.26 (s,6H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++.

8,8-dimethyl-2-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:2′,3′-d]pyrimidin-5-one

MS (ESI): 331 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.69-8.68 (d, J=4.38 Hz,1H), 8.60-8.57 (d, J=8.07 Hz, 1H), 7.78-7.72 (d, J=7.64 Hz, J=1.70 Hz,1H), 7.67-7.64 (d, J=8.07 Hz, 2H), 7.36-7.31 (m, 1H), 3.82 (m, 2H),3.16-3.11 (t, J=7.11 Hz, 2H), 1.81-1.76 (t, J=7.10 Hz, 2H), 1.13 (s,6H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: +++.

Example 12.4 Synthesis of2-(pyridin-2-ylethynyl)-7,7a,8,9,10,12-hexahydro-5H-pyrido[2,3-d]pyrrolo[1′,2′:4,5]pyrazino[1,2-a]pyrimidin-5-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 344 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.69-8.68 (d, J=4.56 Hz, 1H), 8.61-8.59 (d,J=8.10 Hz, 1H), 7.78-7.72 (t, J=7.64 Hz, 1H), 7.69-7.64 (t, J=5.6 Hz,2H), 7.36-7.32 (m, 1H), 4.55-4.49 (dd, J=13.36, 3.87 Hz, 1H), 4.40-4.35(d, J=17.16 Hz, 1H), 3.64-3.49 (m, 2H), 3.35-3.26 (m, 1H), 2.65-2.55 (m,1H), 2.46-2.37 (m, 1H), 2.28-2.10 (m, 1H), 2.06-1.94 (m, 2H), 1.72-1.65(m, 1H).

Example 12.5 Synthesis of2-(pyridin-2-ylethynyl)-8,9,10,11-tetrahydropyrido[2′,3′:4,5]pyrimido[1,2-a]azepin-5(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 2.2a and Example 1.1. MS (ESI): 317 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.69-8.68 (m, 1H), 8.57-8.56 (d, J=8.07 Hz, 1H),7.79-7.72 (m, 1H), 7.68-7.65 (m, 2H), 7.36-7.32 (m, 1H), 4.41-4.38 (m,2H), 3.19-3.16 (m, 2H), 1.91-1.84 (m, 6H). mGluR5 PAM EC₅₀: +.

Example 13.1 Synthesis of8-((3-fluorophenyl)ethynyl)-3-(1-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

8-((3-fluorophenyl)ethynyl)-3-vinyl-4H-pyrido[1,2-a]pyrimidin-4-one (30mg, 0.1 mmol) was added into a saturated HO/ethanol (5 mL) solution.After stirring at ambient temperature for 3 h, the solution was adjustedto pH=8 and extracted with ethyl acetate (3×50 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated to give the crudeproduct, which was purified by column chromatography. MS (ESI): 309(MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 9.01-8.99 (d, J=7.44 Hz, 1H), 8.38 (s,1H), 7.77 (s, 1H), 7.45-7.39 (m, 2H), 7.33-7.28 (m, 1H), 7.20 (m, 1H),7.17 (m, 1H), 5.11-5.02 (m, 1H), 3.54-3.52 (d, J=6.03 Hz, 1H), 2.62-2.57(d, J=6.6 Hz, 3H). mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM: +.

Example 13.2 Synthesis of3-(1-ethoxyethyl)-8-((3-fluorophenyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 4.25. MS (ESI): 337 (M+H⁺); ¹H NMR (300 MHz,CDCl₃) δ 9.02-9.00 (d, J=7.44 Hz, 1H), 8.49 (s, 1H), 7.77 (s, 1H),7.42-7.38 (m, 2H), 7.32-7.29 (m, 1H), 7.20-7.13 (m, 2H), 4.89-4.83 (q,J=6.45 Hz, 1H), 3.56-3.49 (t, J=7.01 Hz, 2H), 1.52-1.50 (d, J=6.45 Hz,3H) 1.30-1.23 (t, J=7.01 Hz, 3H). mGluR5 PAM EC₅₀: +++++. Fold shift at10 μM: ++.

Example 13.3 Synthesis of8-((3-fluorophenyl)ethynyl)-3-Vinyl-4H-pyrido[1,2-a]pyrimidin-4-one

A solution of3-(2-bromoethyl)-8-((3-fluorophenyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one(289 mg, 0.78 mmol) and EtONa (208 mg, 3.05 mmol) in EtOH (absolute) wasstirred at 50° C. for 3 hr. After the suspension was diluted with water(30 mL) and extracted with ethyl acetate (3×50 mL), the combined organiclayers were dried over Na₂SO₄ and concentrated to give the desiredproduct, which was purified by column chromatography. MS (ESI): 291(MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 9.10-9.07 (d, J=7.44 Hz, 1H), 8.44 (s,1H), 7.76 (s, 1H), 7.42-7.39 (m, 2H), 7.32-7.31 (m, 1H), 7.20-7.17 (m,2H), 6.86-6.76 (m, 1H), 6.36-6.29 (dd, J=17.65, 1.38 Hz, 1H), 5.50-5.46(dd, J=11.41, 1.32 Hz, 1H).

Example 13.4 Synthesis of methyl8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate

Example 13.4a Synthesis of dimethyl 2-((dimethylamino)methylene)malonate

A solution of dimethyl malonate (5 g, 37.9 mmol, 1 equiv) in DMF-DMA(11.3 g, 94.8 mmol, 2.5 equiv) was stirred at room temperatureovernight. Then the reaction mixture was concentrated to give 7 g of thedesired product, which was directly used for the next step withoutfurther purification. MS (ESI): 188 (MH⁺).

Example 13.4b Synthesis of dimethyl2-((4-bromopyridin-2-ylamino)methylene)malonate

A solution of dimethyl 2-((dimethylamino)methylene)malonate (11.5 g, 65mmol, 2.2 equiv) and 4-bromopyridin-2-amine (5 g, 28.9 mmol, 1 equiv) inAcOH (40 mL) was stirred at room temperature for 24 h. Then the reactionmixture was diluted with water, filtered, the filter cake was dried togive 4.8 g of the desired product. MS (ESI): 315, 317 (MH⁺).

Example 13.4c Synthesis of methyl8-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate

A mixture of dimethyl 2-((4-bromopyridin-2-ylamino)methylene)malonate(4.8 g, 15.2 mmol, 1 equiv) and POBr₃ (16.1 g, 56.1 mmol, 3.7 equiv) wasstirred at 80° C. for 2 h. After it was cooled to room temperature, thereaction mixture was poured into water carefully. Then the solution wasadjusted pH to 8 with aq. Na₂CO₃ and extracted with DCM (3×200 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated to give3.4 g of the desired product. MS (ESI): 283, 285 (MH⁺).

Example 13.4d Synthesis of methyl8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 323 (MH⁺).

Example 13.5 Synthesis ofN-ethyl-8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide

Example 13.5a Synthesis of8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylicacid

A solution of methyl8((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3carboxylate (100 mg, 0.3 mmol, 1 equiv) in 1% NaOH (2.4 mL, 0.6 mmol, 2equiv) and THF was stirred at room temperature overnight. Then thereaction mixture was adjusted pH to 3 with 10% aq. HCl and filtered togive 40 mg of the desired product. MS (ESI): 309 (MH⁺).

Example 13.5b Synthesis ofN-ethyl-8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide

To a solution of8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylicacid (50 mg, 0.62 mmol, 1 equiv) and Et₃N (0.5 mL) in CHCl₃ (20 mL) at0° C. was added ethyl chloroformate (0.4 mL) dropwise. After thereaction mixture was stirred for 10 min, aq. ethanamine (3 mL) wasadded. Then the mixture was stirred for 10 min and extracted with CHCl₃(3×30 mL), dried over Na₂SO₄ and concentrated to give the desiredproduct (30 mg). MS (ESI): 336 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 9.37 (s,1H), 9.17-9.14 (d, J=7.32 Hz, 1H), 8.96-8.95 (m, 1H), 7.91 (s, 1H),7.44-7.40 (m, 2H), 7.37-7.31 (m, 2H), 7.23-7.18 (m, 1H), 3.60-3.50 (m,2H), 1.32-1.27 (t, J=7.2 Hz, 3H). mGluR5 PAM EC₅₀: ++++.

Example 13.6 Synthesis of8-((3-fluorophenyl)ethynyl)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

Example 13.6a Synthesis of8-bromo-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

To a solution of methyl8-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1 g, 3.5 mmol, 1equiv) in anhydrous THF (25 mL) was added DIBAL-H (5 mL) at 0° C.dropwise. After stirring for 1 h, the reaction mixture was quenched withsaturated NH₄Cl. The solution was extracted with ethyl acetate (3×150mL). The combined organic layers were dried over Na₂SO₄ and concentratedto give the crude product. The crude was purified by columnchromatography to give 145 mg of the desired product. MS (ESI): 255, 257(MH⁺).

Example 13.6b Synthesis of8-((3-fluorophenyl)ethynyl)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 295 (MH⁺); ¹H NMR (300 MHz,CD₃OD) δ 9.03-9.01 (d, J=7.47 Hz, 1H), 8.42 (s, 1H), 7.79 (s, 1H),7.50-7.46 (m, 2H), 7.41-7.35 (m, 2H), 7.28-7.23 (m, 1H), 4.67 (s, 2H).mGluR5 PAM EC₅₀: +.

Example 13.7 Synthesis of8-((3-fluorophenyl)ethynyl)-3-(methoxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

To a solution of8-((3-fluorophenyl)ethynyl)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one(16 mg) in anhydrous THF (5 mL) was added NaH (16 mg, 60% in oil) inportions. After the reaction mixture was stirred for 15 min, MeI (0.05mL) was added. The solution was stirred for 30 min. Then the reactionmixture was quenched with saturated NH₄Cl and extracted with ethylacetate (3×50 mL). The combined organic layers were dried over Na₂SO₄and concentrated to give the desired product (11 mg), which was purifiedby preparative HPLC. MS (ESI): 309 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ9.07-9.05 (d, J=6.81 Hz, 1H), 8.42 (s, 1H), 7.83 (s, 1H), 7.51-7.48 (m,2H), 7.44-7.39 (m, 2H), 7.29-7.27 (m, 1H), 4.53 (s, 2H), 3.54-3.50 (d,J=7.02 Hz, 3H). mGluR5 PAM EC₅₀: +++.

Example 13.8 Synthesis of3-(ethoxymethyl)-8-((3-fluorophenyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 13.7. MS (ESI): 323 (MH⁺); ¹H NMR (300 MHz,CD₃OD) δ 9.06-9.03 (d, J=7.50 Hz, 1H), 8.42 (s, 1H), 7.82 (s, 1H),7.54-7.48 (m, 2H), 7.44-7.38 (m, 2H), 7.30-7.23 (m, 1H), 4.57 (s, 2H),3.70-3.63 (q, 2H), 1.30-1.17 (t, 3H). mGluR5 PAM EC₅₀: +++. Fold shiftat 10 μM: ++.

Example 13.9 Synthesis of8-((3-fluorophenyl)ethynyl)-3-(2-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

Example 13.9a Synthesis of sodium(2-oxodihydrofuran-3(2H)-ylidene)methanolate

Three-neck, round-bottomed flask equipped with mechanical stirrer,addition funnel, and reflux condenser was placed in a hood behind ashield. The condenser was fitted with a drying tube which was connectedto a mineral oil bubble chamber so hydrogen evolution could bemonitored. After NaH (4.4 g of 60% oil dispersion, 0.11 mol) was washedwith n-C₆H₁₄ (2×50 mL), filtered with brief suction drying, andtransferred to the flask, sufficient Et₂O was added to cover theresulting solid. A catalytic amount of C₂H₅OH (ca. 2 drops) was addeddirectly to the Et₂O—NaH suspension and dropwise addition withoutstirring of a solution of dihydrofuran-2(3H)-one (8.61 g, 0.1 mol) andethyl formate (7.41 g, 0.1 mol) in Et₂O (10 mL) was started. As soon asthe Et₂O began to reflux, additional Et₂O (50-60 mL) was rapidly addedthrough the reflux condenser and stirring was started. Lactone-formateaddition was complete in 1 hr, and stirring was continued for anadditional 22 h. Filtration, washing with Et₂O, and vacuum drying gavedesired product (14.0 g) as a fine powdery solid.

Example 13.9b Synthesis of3-((4-bromopyridin-2-ylamino)methylene)dihydrofuran-2(3H)-one

A solution of sodium (2-oxodihydrofuran-3(2H)-ylidene)methano-late (134mg, 1 mmol), 4-bromopyridin-2-amine (173 mg, 1.0 mmol) and4-methylbenzenesulfonic acid (50 mg, 0.29 mmol) in toluene was stirredat 150° C. for 1 hr. After the suspension was diluted with water, thesolution was adjusted to pH 8 and extracted with ethyl acetate. Then,the organic layers were dried over Na₂SO₄ and concentrated to give crudeproduct, which was used for then next reaction without furtherpurification. MS (ESI): 269, 271 (MH⁺).

Example 13.9c Synthesis of8-bromo-3-(2-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

In a small flask,3-((4-bromopyridin-2-ylamino)methylene)dihydrofuran-2(3H)-one (250 mg,0.93 mmol) and CF₃COOH (8 drops) was added into a solution of xylene.The suspension was warmed to 85° C. and maintained at that temperaturefor 30 min. After the upper layer of suspension was poured out, theresidue was diluted with water (30 mL) and adjusted to pH 8. Then themixture was extracted with ethyl acetate (3×50 mL). The organic layerwas dried over Na₂SO₄ and concentrated to give the crude product, whichwas purified by column chromatography. MS (ESI): 269, 271 (MH⁺).

Example 13.9d Synthesis of8-((3-fluorophenyl)ethynyl)-3-(2-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 309 (MH⁺); ¹H NMR (300 MHz,CDCl₃+D₂O) δ 9.02-8.99 (d, J=7.41 Hz, 1H), 8.31 (s, 1H), 7.76 (s, 1H),7.42-7.40 (m, 2H), 7.32-7.28 (m, 1H), 7.20-7.14 (m, 2H), 3.99-3.93 (t,J=5.70 Hz, 2H), 2.99-2.94 (t, J=5.70 Hz, 2H).

Example 13.10 Synthesis of8-((3-fluorophenyl)ethynyl)-3-(2-methoxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 13.7. MS (ESI): 323 (MH⁺); ¹H NMR (300 MHz,DMSO-d⁶) δ 9.0-8.98 (d, J=7.47 Hz, 1H), 8.31 (s, 1H), 7.73 (s, 1H),7.41-7.39 (m, 2H), 7.31 (s, 1H), 7.18-7.12 (m, 2H), 3.72-3.68 (t, J=6.35Hz, 2H), 3.38 (s, 3H), 2.97-2.93 (t, J=6.38 Hz, 2H). mGluR5 PAM EC₅₀:++++. Fold shift at 10 μM: ++.

Example 13.11 Synthesis of8-((4-fluorophenyl)ethynyl)-3-(2-methoxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 13.7. MS (ESI): 323 (MH⁺); ¹H NMR (300 MHz,DMSO-d⁶) δ 9.0-8.97 (d, J=7.48 Hz, 1H), 8.30 (s, 1H), 7.71 (s, 1H),7.62-7.58 (m, 2H), 7.15-7.09 (m, 3H), 3.72-3.68 (t, J=6.36 Hz, 2H), 3.38(s, 3H), 2.97-2.93 (t, J=6.35 Hz, 2H). mGluR5 PAM EC₅₀: ++++. Fold shiftat 10 μM: ++.

Example 13.12 Synthesis of3-(2-methoxyethyl)-8-(pyridin-2-ylethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 13.7. MS (ESI): 306 (MH⁺); ¹H NMR (300 MHz,CD₃OD) δ 9.29-9.27 (d, J=7.47 Hz, 1H), 8.78-8.77 (d, J=4.92 Hz, 1H),8.44 (s, 1H), 8.33-8.31 (d, J=7.02 Hz, 2H), 8.23-8.18 (t, J=7.74 Hz,1H), 8.15-8.10 (t, J=7.32 Hz, 1H), 7.68-7.63 (t, J=6.36 Hz, 1H),3.75-3.71 (t, J=6.09 Hz, 1H), 3.38 (s, 3H), 2.98-2.94 (t, J=7.08 Hz,2H).

Example 13.13 Synthesis of3-(2-ethoxyethyl)-8-((3-fluorophenyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 13.7. MS (ESI): 337 (MH⁺); ¹H NMR (300 MHz,DMSO-d⁶) δ 9.0-8.98 (d, J=7.44 Hz, 1H), 8.32 (s, 1H), 7.73 (s, 1H),7.41-7.38 (m, 2H), 7.33-7.28 (m, 1H), 7.18-7.11 (m, 2H), 3.76-3.71 (t,J=6.35 Hz, 2H), 3.57-3.50 (q, 2H), 2.98-2.93 (t, J=7.00 Hz, 2H),1.23-1.18 (t, 3H). mGluR5 PAM EC₅₀: +++. Fold shift at 10 μM: ++.

Example 13.14 Synthesis of the HCl salt of3-(2-(dimethylamino)ethyl)-8-((3-fluorophenyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one

Example 13.14a Synthesis of8-bromo-3-(2-bromoethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

3-((4-bromopyridin-2-ylimino)methyl)dihydrofuran-2(3H)-one (800 mg, 2.97mmol) and POBr₃ (4 g, 13.9 mmol) was stirred at 80° C. for 1.5 hr. Afterthe suspension was poured into ice water, the solution was adjusted topH 8 and extracted with DCM (3×100 mL). The combined organic layers werewashed with brine and concentrated to give 850 mg crude product, whichwas directly used for the next step without further purification. MS(ESI): 330, 332, 334 (MH⁺).

Example 13.14b Synthesis of3-(2-bromoethyl)-8-((3-fluorophenyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 371, 373 (MH⁺).

Example 13.14c Synthesis of the HCl salt of3-(2-(dimethylamino)ethyl)-8-((3-fluorophenyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one

A solution of3-(2-bromoethyl)-8-((3-fluorophenyl)ethynyl)-4H-pyrido-[1,2-a]pyrimidin-4-one(240 mg, 0.65 mmol), 30% aq. dimethylamine (0.3 mL) and K₂CO₃ (0.5 g,3.6 mmol) in CH₃CN was stirred at room temperature for 3 hr. Thesolution was diluted with water (30 mL) and extracted with ethyl acetate(3×50 mL). Then the combined organic layers were concentrated to givethe desired product, which was purified by column chromatography. Theproduct was then converted to the corresponding HCl salt. MS (ESI): 336(MH⁺). ¹H NMR (300 MHz, CDCl₃) δ 9.0-8.97 (d, J=7.47 Hz, 1H), 8.29 (s,1H), 7.72 (s, 1H), 7.41-7.38 (m, 2H), 7.31-7.28 (m, 1H), 7.19-7.11 (m,2H), 2.88-2.83 (m, 2H), 2.67-2.62 (m, 2H), 2.33 (s, 6H).

Example 13.15 Synthesis of8-((3-fluorophenyl)ethynyl-3-(2-pyrrolidin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 13.14b. MS (ESI): 362 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 9.00-8.98 (d, J=7.41, Hz, 1H), 8.30 (s, 1H), 7.72 (s, 1H),7.41-7.38 (m, 2H), 7.3-7.28 (m, 1H), 7.19-7.11 (m, 2H), 2.93-2.87 (m,2H), 2.83-2.77 (m, 2H), 2 2.62 (broad, 4H), 1.84-1.79 (m, 4H).

Example 13.16 Synthesis of8-((3-fluorophenyl)ethynyl)-3-(2-morpholinoethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 13.14b. MS (ESI): 378 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 9.0-8.98 (d, J=7.44 Hz, 1H), 8.30 (s, 1H), 7.73 (s, 1H),7.42-7.38 (m, 2H), 7.32-7.29 (m, 1H), 7.20-7.12 (m, 2H), 3.75 (broad,4H), 2.90-2.85 (m, 2H), 2.72-2.68 (m, 2H), 2.62-2.57 (m, 4H).

Example 13.17 Synthesis of8-((3-fluorophenyl)ethynyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

Example 13.17a Synthesis of8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbonylchloride

To a mixture of8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylicacid (50 mg, 0.162 mmol, 1 equiv) and 1 drop DMF in dichloromethane wasadded oxalyl dichloride (1 mL) dropwise. The reaction mixture wasstirred at room temperature for 3 h and concentrated to give the desiredproduct, which was directly used for the next step.

Example 13.17b Synthesis of8-((3-fluorophenyl)ethynyl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbonylchloride was dissolved in 1,4-dioxane (3 mL). To the solution was addedacetamidine hydrochloride (18 mg, 0.162 mmol, 1 equiv) and pyridine (2mL). The reaction mixture was then heated at 70° C. overnight. After itwas cooled to room temperature, the reaction mixture was diluted withwater and extracted with ethyl acetate (3×50 mL). The combined organiclayers were dried over Na₂SO₄. After filtration and concentration, theresidue was purified by preparative TLC to give 2.2 mg of the desiredproduct. MS (ESI): 347 (MH⁺).

Example 13.18 Synthesis of8-((3-fluorophenyl)ethynyl)-3-(2-hydroxypropan-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

Example 13.18a Synthesis of8-bromo-3-(2-hydroxypropan-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

To a solution of methyl8-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (200 mg, 0.71mmol, 1 equiv) in THF (10 mL) was added methylmagnesium bromide (0.78mL, 1 M, 0.77 mmol, 2.2 equiv) at 0° C. dropwise. After the reactionmixture was stirred for 0.5 h, it was quenched with 10% HCl andextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over Na₂SO₄. After filtration and concentration, the residue waspurified by preparative HPLC to give 35 mg of the desired product. MS(ESI): 283, 285 (MH⁺).

Example 13.18b Synthesis of8-((3-fluorophenyl)ethynyl)-3-(2-hydroxypropan-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 265 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.50-8.47 (d, J=6.84 Hz, 1H), 8.41 (m, 1H), 8.02 (s, 1H),7.46-7.41 (m, 2H), 7.34-7.31 (m, 2H), 7.22-7.16 (m, 1H), 1.70 (s, 6H).mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM: +.

Example 14.1 Synthesis of6-(pyridin-2-ylethynyl)-2,3-dihydrocyclopenta[d]pyrido[1,2-a]pyrimidin-10(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1. MS (ESI): 288 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 9.06-9.04 (d, J=7.41 Hz, 1H), 8.71-8.69 (d, J=3.30 Hz, 1H),7.80-7.75 (m, 2H), 7.64-7.62 (d, J=7.80 Hz, 1H), 7.38-7.34 (m, 1H),7.19-7.17 (dd, J=7.41, 1.80 Hz, 1H), 3.09-3.01 (m, 4H), 2.24-2.06 (m,2H).

Example 15.1 Synthesis of7-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrido[2,1-b]quinazolin-11(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1. MS (ESI): 302 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.92-8.90 (d, J=7.47 Hz, 1H), 8.70-8.68 (d, J=4.86 Hz, 1H),7.79-7.74 (t, J=7.74 Hz, 1H), 7.70 (s, 1H), 7.63-7.60 (d, J=7.80 Hz,1H), 7.37-7.32 (m, 1H), 7.11-7.07 (d, J=7.44 Hz, 1H), 2.85-2.81 (m, 2H),2.77-2.73 (m, 2H), 1.94-1.84 (m, 4H). mGluR5 PAM EC₅₀: +++.

Example 15.2 Synthesis of3-methyl-7-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrido[2,1-b]quinazolin-11(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1. MS (ESI): 316 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.92-8.89 (d, J=7.44 Hz, 1H), 8.69-8.68 (d, J=4.32 Hz, 1H),7.78-7.73 (t, J=7.74 Hz, 1H), 7.69 (s, 1H), 7.62-7.59 (d, J=7.80 Hz,1H), 7.36-7.32 (t, J=7.58 Hz, 1H), 7.10-7.07 (d, J=7.46 Hz, 1H),2.96-2.85 (m, 2H), 2.69-2.57 (m, 1H), 2.50-2.41 (m, 1H), 2.01-1.95 (m,2H), 1.47-1.33 (m, 1H), 1.13-1.11 (d, J=6.48 Hz, 3H). mGluR5 PAM EC₅₀:+++++. Fold shift at 10 μM: +++.

Example 15.3 Synthesis of3,3-dimethyl-7-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrido[2,1-b]quinazolin-11(2H)-one

Example 15.3a Synthesis of methyl 4,4-dimethyl-2-oxocyclohexanecarboxylate

A solution of 3,3-dimethylcyclohexanone (0.5 g, 3.97 mmol, 1 equiv) andsodium hydride in toluene was stirred at rt for half an hour. To themixture was added dimethyl carbonate and heated at reflux for 5 h. Afterthe reaction was cooled to rt, the reaction mixture was quenched withwater and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine and dried over anhydrous sodium sulfate,then concentrated under reduced pressure to give the crude product,which was directly used for the next step.

Example 15.3b Synthesis of7-bromo-3,3-dimethyl-3,4-dihydro-1H-pyrido[2,1-b]quinazolin-11(2H)-one

A solution of methyl 4,4-dimethyl-2-oxocyclohexanecarboxylate (0.5 g,2.7 mmol, 1 eq), 4-bromopyridin-2-amine (0.51 g, 2.97 mmol, 1.1 eq) andPPA in 1,2-dichloroethane was stirred at 80° C. for 4 hours. After itwas cooled to rt, the reaction mixture was quenched with saturatedNa₂CO₃ and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine and dried over anhydrous sodium sulfate.After filtration and concentration, the residue was purified by silicagel chromatography to give the desired product.

Example 15.3c Synthesis of3,3-dimethyl-7-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrido[2,1-b]quinazolin-11(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 330 (M+H⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.93-8.91 (d, J=7.44 Hz, 1H), 8.70-8.68 (d, J=4.65 Hz, 1H),7.79-7.74 (t, J=7.74 Hz, 1H), 7.70 (s, 1H), 7.63-7.60 (d, J=7.80 Hz,1H), 7.37-7.33 (t, J=6.62 Hz, 1H), 7.09-7.08 (d, J=7.44 Hz, 1H),2.80-2.62 (m, 2H), 2.62 (s, 2H), 1.69-1.61 (m, 2H), 1.05 (s, 6H). mGluR5PAM EC₅₀: +++++. Fold shift at 10 μM: +++.

Example 15.4 Synthesis of2,2-dimethyl-7-(pyridin-2-ylethynyl)-3,4-dihydro-1H-Pyrido[2,1-b]quinazolin-11(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 15.3a, Example 15.3b, and Example 1.1. MS (ESI):330 (M+H⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.93-8.90 (d, J=7.44 Hz, 1H),8.70-8.69 (d, J=4.71 Hz, 1H), 7.79-7.74 (t, J=7.77 Hz, 1H), 7.70 (s,1H), 7.63-7.60 (d, J=7.83 Hz, 1H), 7.37-7.33 (t, J=6.77 Hz, 1H),7.11-7.08 (dd, J=7.44, 1.65 Hz, 1H), 2.89-2.85 (t, J=6.62 Hz, 2H), 2.55(s, 2H), 1.70-1.65 (t, J=6.62 Hz, 2H) 1.06 (s, 6H). mGluR5 PAM EC₅₀:+++++. Fold shift at 10 μM: +.

Example 15.5 Synthesis of8-(pyridin-2-ylethynyl)-2,3,13,13a-tetrahydro-1H-pyrido[1′,2′:1,2]pyrimido[4,5-f]indolizin-12(5H)-one

Example 15.5a Synthesis of tert-butyl 2-formylpyrrolidine-1-carboxylate

To a solution of 1-tert-butyl 2-methyl pyrrolidine-1,2-dicarboxylate(3.5 g, 15.3 mmol) in toluene at −78° C. was added DIBAL-H (17.6 mL, 30mmol, 1.7 M) dropwise while maintaining the reaction temperature below−65° C. The reaction was stirred at −78° C. for 2 h and then quenchedwith methanol (10 mL). The mixture was then diluted with ethyl acetate(50 mL), saturated NH₄Cl was added, and the mixture was stirredvigorously for 20 min at room temperature. The two phases were thenseparated and the aqueous layer was extracted with DCM (2×50 mL). Thecombined organics were then washed with brine, dried over Na₂SO₄,concentrated under reduced pressure and purified by columnchromatography to give 3 g of the desired product. MS (ESI): 200 (MH⁺).

Example 15.5b Synthesis of tert-butyl2-(3-ethoxy-3-oxoprop-1-enyl)pyrrolidine-1-carboxylate

A solution of tert-butyl 2-formylpyrrolidine-1-carboxylate (4 g, 20mmol) and (carbethoxymethylene)triphenylphosphorane (7 g, 20 mmol) inTHF was stirred at room temperature for 2 hr. Then the mixture wasconcentrated and purified by column chromatography to give 4 g ofdesired product. MS (ESI): 270 (MH⁺).

Example 15.5c Synthesis of tert-butyl2-(3-ethoxy-3-oxopropyl)pyrrolidine-1-carboxylate

A solution of tert-butyl2-(3-ethoxy-3-oxoprop-1-enyl)pyrrolidine-1-carboxylate (4 g, 14.9 mmol)and Pd/C (1 g, 10% weight) in MeOH was stirred at room temperature.Hydrogen from a balloon was ventilated to the suspension continuouslyand the completion of the reaction was monitored by TLC. After thesuspension was filtered, the organic phases was concentrated to give thedesired product, which was directly used for the next step withoutfurther purification. MS (ESI): 272 (MH⁺).

Example 15.5d Synthesis of ethyl-3-(pyrrolidin-2-yl)propanoate

The title compound was prepared according to the experimental procedureas described in Example 1.21c. MS (ESI): 172 (MH⁺).

Example 15.5e Synthesis of ethyl3-(1-(2-methoxy-2-oxoethyl)pyrrolidin-2-yl)propanoate

A solution of ethyl 3-(pyrrolidin-2-yl) propanoate (3 g, 17.5 mmol),methyl 2-bromoacetate (3 g, 18 mmol) and K₂CO₃ (3 g, 21.7 mmol) in CH₃CNwas stirred at 80° C. overnight. The completion of the reaction wasmonitored by TLC. After the suspension was diluted with water (50 mL)and extracted with ethyl acetate (3×50 mL), the combined organic layerswere concentrated to give the crude product, which was directly used forthe next step without further purification. MS (ESI): 244 (MH⁺).

Example 15.5f Synthesis of ethyl 6-oxooctahydroindolizine-7-carboxylate

A solution of ethyl3-(1-(2-methoxy-2-oxoethyl)pyrrolidin-2-yl)propanoate (2 g) and NaH (2g, 60% weight) in DMF was stirred at 40° C. for 10 mins. The completionof reaction was monitored by TLC. After the suspension was quenched withwater (30 mL), the solution was extracted with ethyl acetate (3×100 mL)and the combined organic layer was washed with brine, dried over Na₂SO₄.The desired product (230 mg) was obtained by column chromatography. MS(ESI): 212 (MH⁺).

Example 15.5g. Synthesis of8-bromo-2,3,13,13a-tetrahydro-1H-pyrido[1′,2′:1,2]pyrimido[4,5-f]indolizin-12(5H)-one

A solution of ethyl 6-oxooctahydroindolizine-7-carboxylate (230 mg, 1.1mmol), 4-bromopyridin-2-amine (188 mg, 1.1 mmol) and excess PPA (2 g) in1,2-dichloroethane was stirred at 80° C. overnight. After the suspensionwas diluted with water (20 mL) and adjusted to pH 8. The mixture wasextracted with ethyl acetate (3×50 mL) and the combined organic layerswere concentrated to give the crude product. 70 mg of the desiredproduct was obtained after column chromatography. MS (ESI): 320, 322(MH⁺).

Example 15.5h Synthesis of8-(pyridin-2-ylethynyl)-2,3,13,13a-tetrahydro-1H-pyrido[1′,2′:1,2]pyrimido[4,5-f]indolizin-12(5H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 343 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.78-8.76 (d, J=7.53 Hz, 1H), 8.68-8.66 (d, J=4.77 Hz, 1H),7.77-7.71 (t, J=7.76 Hz, 1H), 7.62-7.57 (m, 2H), 7.34-7.29 (m, 1H),6.98-6.95 (d, J=7.58 Hz, 1H), 4.38 (m, 1H), 3.66-3.43 (m, 3H), 2.99-2.90(m, 2H), 2.26-2.20 (m, 1H), 2.12-2.06 (m, 1H), 2.02-1.95 (m, 2H),1.16-1.15 (m, 1H).

Example 15.6 Synthesis of2-(11-oxo-7-(pyridin-2-ylethynyl)-3,4-dihydro-1H-dipyrido[1,2-a:4′,3′-d]pyrimidin-2(11H)-yl)acetonitrile

Example 15.6a Synthesis of7-bromo-3,4-dihydro-1H-dipyrido[1,2-a:4′,3′-d]pyrimidin-11(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1a.

Example 15.6b Synthesis of2-(11-oxo-7-bromo-3,4-dihydro-1H-dipyrido[1,2-a:4′,3′-d]pyrimidin-2(11H)-yl)acetonitrile

The title compound was prepared according to the experimental procedureas described in Example 5.6a.

Example 15.6c Synthesis of2-(11-oxo-7-(pyridin-2-ylethynyl)-3,4-dihydro-1H-dipyrido[1,2-a:4′,3′-d]pyrimidin-2(11H)-yl)acetonitrile

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 315 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.94-8.92 (d, J=7.41 Hz, 1H), 8.71-8.69 (d, J=3.93 Hz, 1H),7.80-7.74 (m, 2H), 7.64-7.61 (d, J=7.65 Hz, 1H), 7.38-7.34 (t, J=4.92Hz, 1H), 7.17-7.15 (d, J=7.38 Hz, 1H), 3.81-3.78 (d, J=3.39 Hz, 4H),3.03-2.99 (m, 4H). mGluR5 PAM EC₅₀: +.

Example 15.7 and Example 15.8 Synthesis of(S)-10-(pyridin-2-ylethynyl)-2,3,13,13a-tetrahydro-1H-pyrido[1′,2′:1,2]pyrimido[5,4-f]indolizin-6(5H)-oneand(S)-9-(pyridin-2-ylethynyl)-2,3,5,6-tetrahydro-1H-pyrido[1′,2′:1,2]pyrimido[4,5-g]indolizin-13(13bH)-one

The title compounds were prepared according to the experimentalprocedure as described in Example 15.5f, Example 15.5g, and Example 1.1.MS (ESI): 343 (MH⁺).

(S)-10-(pyridin-2-ylethynyl)-2,3,13,13a-tetrahydro-1H-pyrido[1′,2′:1,2]pyrimido[5,4-f]indolizin-6(5H)-one

¹H NMR (300 MHz, CDCl₃) δ 8.95-8.93 (d, J=7.50 Hz, 1H), 8.70-8.69 (d,J=4.80 Hz, 1H), 7.80-7.74 (m, 2H), 7.63-7.61 (d, J=7.80 Hz, 1H),7.38-7.33 (m, 1H), 7.15-7.12 (dd, J=7.44, 1.47 Hz, 1H), 4.36-4.31 (d,J=16.2 Hz, 1H), 3.40-3.33 (t, J=8.65 Hz, 1H), 3.29-3.24 (d, J=16.2 Hz,1H), 3.07-3.01 (dd, J=16.2, 2.87 Hz, 1H), 2.85-2.76 (m, 1H), 2.48-2.43(m, 1H), 2.40-2.34 (m, 1H), 2.19-2.14 (m, 1H), 2.00-1.88 (m, 2H),1.59-1.58 (m, 1H). mGluR5 PAM EC₅₀: +.

(S)-9-(pyridin-2-ylethynyl)-2,3,5,6-tetrahydro-1H-pyrido[1′,2′:1,2]pyrimido[4,5-g]indolizin-13(13bH)-one

¹H NMR (300 MHz, CDCl₃) δ 8.93-8.91 (d, J=7.47 Hz, 1H), 8.71-8.69 (d,J=4.47 Hz, 1H), 7.80-7.74 (m, 2H), 7.64-7.61 (d, J=7.77 Hz, 1H),7.38-7.34 (t, J=6.69 Hz, 1H), 7.17-7.14 (d, J=7.46 Hz, 1H), 4.18 (broad,1H), 3.57 (broad, 1H), 3.16-3.05 (m, 4H), 2.85-2.74 (m, 1H), 2.06-1.96(m, 2H), 1.82-1.69 (m, 2H).

Example 16.1 Synthesis of3-((4-fluorophenyl)ethynyl)-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one

Example 16.1a Synthesis of3-bromo-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one

A mixture of methyl 2-oxocycloheptanecarboxylate (2 g, 11.8 mmol) and4-bromopyridin-2-amine (2.04 g, 11.8 mmol), and PPA (5 mL) in1,2-dichloroethane (10 mL) was stirred at 85° C. for 5 h. The reactionmixture was cooled to ambient temperature. A chilled saturated sodiumcarbonate solution was added to adjust pH to 8. The resulting mixturewas extracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine and dried over anhydrous sodium sulfate. Afterfiltration and concentration, the crude product was purified by silicagel chromatography to produce 2.4 g of the desired product. MS (ESI):293 (MH⁺).

Example 16.1b Synthesis of3-(4-fluoro-phenylethynyl)-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one

A solution of3-bromo-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one(250 mg, 0.85 mmol), 1-ethynyl-4-fluorobenzene (255 mg, 2.12 mmol),Pd(OAc)₂ (38.2 mg, 0.17 mmol), PPh₃ (200 mg, 0.76 mmol), CuI (16.2 mg,0.085 mmol), and Et₃N (0.7 mL) in DMF (8 mL) was stirred in a sealedtube at 70° C. for 3.5 hours. After it was cooled to room temperature,the reaction mixture was diluted with H₂O and extracted with ethylacetate (2×50 mL). The combined organic layers were washed with brineand dried over anhydrous sodium sulfate. After filtration andconcentration, the crude product was purified by silica gel to produce185 mg of desired product. MS (ESI): 333 (MH⁺); ¹H NMR (300 MHz, CDCl₃)δ 8.97-8.94 (dd, J=7.44, 0.66 Hz, 1H), 7.65-7.56 (m, 3H), 7.15-7.06 (m,3H), 3.00-2.97 (m, 4H), 1.94-1.88 (m, 2H), 1.80-1.64 (m, 4H). mGluR5 PAMEC₅₀: +++++. Fold shift at 10 μM: +.

Example 16.2 Synthesis of3-(phenylethynyl)-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one

The title compound was prepared according to the experimental asdescribed in Example 16.1b. MS (ESI): 315 (MH⁺); ¹H NMR (300 MHz, CDCl₃)δ 8.97-8.95 (d, J=7.50 Hz, 1H), 7.67-7.66 (d, J=1.05 Hz, 1H), 7.62-7.58(m, 2H), 7.45-7.39 (m, 2H), 7.12-7.09 (dd, J=7.44 Hz, 1.80 Hz, 1H),3.00-2.70 (m, 4H), 1.79-1.74 (m, 2H), 1.72-1.64 (m, 4H). mGluR5 PAMEC₅₀: +++++. Fold shift at 10 μM: +.

Example 16.3 Synthesis of3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1b. MS (ESI): 316 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 9.00-8.92 (d, J=7.29 Hz, 1H), 8.75-8.69 (m, 1H), 7.82-7.74 (m,2H), 7.63-7.61 (d, J=7.56 Hz, 1H), 7.46-7.33 (m, 1H), 7.16-7.13 (d,J=8.25 Hz, 1H), 3.05-2.87 (m, 4H), 1.91-1.90 (m, 2H), 1.77-1.66 (m, 4H).mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: +.

Example 16.4 Synthesis of3-(pyridin-3-ylethynyl)-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1b. MS (ESI): 316 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.99-8.96 (d, J=7.41 Hz, 1H), 8.83 (s, 1H), 8.69-8.61 (m, 1H),7.91-7.83 (d, J=7.89 Hz, 1H), 7.69 (s, 1H), 7.43-7.34 (m, 1H), 7.11-7.09(d, J=6.87 Hz, 1H), 3.01-2.97 (m, 4H), 1.92-1.90 (m, 2H), 1.78-1.68 (m,4H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 16.5 Synthesis of3-(pyridin-4-ylethynyl)-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1b. MS (ESI): 316 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.99-8.96 (d, J=7.47 Hz, 1H), 8.70-8.68 (d, J=6.00 Hz, 2H),7.70 (s, 1H), 7.45-7.43 (d, J=6.03 Hz, 2H), 7.10-7.07 (dd, J=7.44, 1.77Hz, 1H), 3.01-2.97 (m, 4H), 1.96-1.88 (m, 2H), 1.79-1.68 (m, 4H). mGluR5PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 16.6 Synthesis of8-methyl-3-(pyridin-2-ylethynyl)-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one

The title compound was prepared according to the experimental proceduresas described in Example 16.1a and Example 16.1b. MS (ESI): 330 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.98-8.96 (d, J=7.35 Hz, 1H), 8.71-8.69 (d,J=5.01 Hz, 1H), 7.80-7.74 (m, 2H), 7.63-7.61 (d, J=7.77 Hz, 1H),7.37-7.30 (m, 1H), 7.16-7.13 (d, J=7.44 Hz, 1H), 3.51-3.44 (m, 1H),3.06-2.94 (m, 2H), 2.51-2.42 (t, J=5.8 Hz, 1H), 2.01-1.94 (m, 2H),1.89-1.85 (m, 1H), 1.29-1.20 (m, 1H), 1.09-1.06 (m, 1H), 1.00-0.98 (d,J=6.60 Hz, 3H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: +++.

Example 16.7 Synthesis of4-fluoro-N-(13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazolin-3-yl)benzamide

Example 16.7a Synthesis of2-bromo-5,7,8,9,10,11-hexahydroazepino[1,2-b]isoquinoline

The title compound was prepared according to the experimental procedureas described in Example 16.1a. MS (ESI): 294, 296 (MH+).

Example 16.7b Synthesis of8-bromo-3-methyl-2,3,4,5-tetrahydropyrido[1′,2′:1,2]pyrimido[4,5-d]azepin-12(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.21d. MS (ESI): 308, 310 (MH⁺).

Example 16.7c Synthesis of8-((4-fluorophenyl)ethynyl)-3-methyl-2,3,4,5-tetrahydropyrido[1′,2′:1,2]pyrimido[4,5-d]azepin-12(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 348 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.97-8.95 (d, J=7.41 Hz, 1H), 7.66 (s, 1H), 7.61-7.57 (m, 2H),7.15-7.09 (t, J=8.78 Hz, 3H), 3.14-3.11 (m, 4H), 2.70-2.60 (m, 4H), 2.42(s, 3H). mGluR5 PAM EC₅₀: +. Fold shift at 10 μM: +++.

Example 17.1 Synthesis of3-(phenylethynyl)-8,9,10,11-tetrahydro-6H-cycloocta[d]pyrido[1,2-a]pyrimidin-12(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1. MS (ESI): 329 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.95-8.93 (dd, J=7.46, 0.68 Hz, 1H), 7.68-7.67 (m, 1H),7.62-7.58 (m, 2H), 7.45-7.38 (m, 3H), 7.09-7.06 (dd, J=7.46, 1.79 Hz,1H), 2.95-2.90 (m, 4H), 1.88-1.78 (m, 4H), 1.52-1.44 (m, 4H). mGluR5 PAMEC₅₀: +++++. Fold shift at 10 μM: +.

Example 17.2 Synthesis of3-(pyridin-2-ylethynyl)-8,9,10,11-tetrahydro-6H-cycloocta[d]pyrido[1,2-a]pyrimidin-12(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1. MS (ESI): 330 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.96-8.94 (dd, J=7.41, 0.69 Hz, 1H), 8.71-8.69 (d, J=4.35 Hz,1H), 7.80-7.74 (m, 2H), 7.63-7.60 (d, J=7.95 Hz, 1H), 7.38-7.28 (m, 1H),7.13-7.10 (dd, J=7.44, 1.80 Hz, 1H), 2.96-2.91 (m, 4H), 1.91-1.78 (m,4H), 1.48 (s, 4H). mGluR5 PAM EC₅₀: +++++.

Example 17.3 Synthesis of3-(pyridin-3-ylethynyl)-8,9,10,11-tetrahydro-6H-cycloocta[d]pyrido[1,2-a]pyrimidin-12(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1. MS (ESI): 330 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.97-8.94 (d, J=7.14 Hz, 1H), 8.83 (s, 1H), 8.66-8.64 (m, 1H),7.90-7.86 (m, 1H), 7.71 (s, 1H), 7.46-7.35 (m, 1H), 7.09-7.06 (dd,J=7.41, 1.71 Hz, 1H), 2.96-2.91 (m, 4H), 1.88-1.78 (m, 4H), 1.48 (m,4H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 17.4 Synthesis of3-(pyridin-4-ylethynyl)-8,9,10,11-tetrahydro-6H-cycloocta[d]pyrido[1,2-a]pyrimidin-12(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1. MS (ESI): 330 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.97-8.95 (dd, J=7.44, 0.66 Hz, 1H), 8.70-8.68 (d, J=6.03 Hz,2H), 7.72 (s, 1H), 7.45-7.43 (d, J=6.06 Hz, 2H), 7.08-7.05 (dd, J=7.46,1.79 Hz, 1H), 2.96-2.91 (m, 4H), 7.88-1.79 (m, 4H), 1.49-1.47 (m, 4H).mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 17.5 Synthesis of3-((4-fluorophenyl)ethynyl)-8,9,10,11-tetrahydro-6H-cycloocta[d]pyrido[1,2-a]pyrimidin-12(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 16.1. MS (ESI): 347 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.95-8.92 (dd, J=7.44, 0.72 Hz, 1H), 7.66 (s, 1H), 7.61-7.56(m, 2H), 7.15-7.04 (m, 3H), 2.95-2.90 (m, 4H), 1.87-1.78 (m, 4H),1.541.48 (m, 4H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: +.

Example 18.1 Synthesis of6-((3-fluorophenyl)ethynyl)isoquinolin-1(2H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 264(MH⁺); ¹H NMR (300 MHz,DMSO-d⁶) δ 11.38 (s, 1H), 8.21 (d, J=8.31 Hz, 1H), 7.91 (s, 1H),7.62-7.59 (m, 1H), 7.55-7.44 (m, 3H), 7.36-7.29 (m, 1H), 7.25 (m, 1H),6.59-6.56 (d, J=7.20 Hz, 1H). mGluR5 PAM EC₅₀: +.

Example 18.2 Synthesis of6-((4-fluorophenyl)ethynyl)-2-propylisoquinolin-1 (2H)-one

The title compound was prepared according to the experimental procedureas described in Example 1.6a and Example 1.1. MS (ESI): 306 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 8.43-8.40 (d, J=8.43 Hz, 1H), 7.68 (s, 1H),7.60-7.54 (m, 3H), 7.11-7.06 (m, 3H), 6.48-6.45 (d, J=7.89 Hz, 1H),4.00-3.95 (t, J=7.50 Hz, 2H), 1.87-1.80 (m, 2H), 1.03-0.98 (t, J=7.34Hz, 3H). mGluR5 PAM EC₅₀: +.

Example 18.3 Synthesis of the HCl salt of3,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrido[1,2-b]isoquinolin-6(2H)-oneand the HCl salt of2,2-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrido[1,2-b]isoquinolin-6(2H)-oneas an 85:15 mixture

Example 18.3a Synthesis of 6-bromoisochroman-1,3-dione

A solution of 4-bromo-2-carboxymethyl-benzoic acid (200 mg, 1.1 mmol) in2 mL acetic anhydride was refluxed for 10 h. Then the mixture wasconcentrated to dryness and the crude 6-bromoisochroman-1,3-dione wasused into the next step without further purification.

Example 18.3b Synthesis of6-methoxy-3,3-dimethyl-2,3,4,5-tetrahydropyridine and6-methoxy-4,4-dimethyl-2,3,4,5-tetrahydropyridine

The title compounds were prepared as a 6:4 mixture according to theexperimental as described in Example 23.2a.

Example 18.3c Synthesis of9-bromo-3,3-dimethyl-3,4-dihydro-1H-pyrido[1,2-b]isoquinolin-6(2H)-oneand9-bromo-2,2-dimethyl-3,4-dihydro-1H-pyrido[1,2-b]isoquinolin-6(2H)-one

6-bromoisochroman-1,3-dione prepared from Example 18.3a and a mixture of6-methoxy-3,3-dimethyl-2,3,4,5-tetrahydropyridine and6-methoxy-4,4-dimethyl-2,3,4,5-tetrahydropyridine (ratio of 6:4,respectively) (200 mg, 1.57 mmol) in 30 mL toluene was refluxed overnight. After the solvent was removed, the crude product was purified bysilica gel chromatography to give desired products (20 mg). MS (ESI):306, 308 (MH⁺).

Example 18.3d Synthesis of HCl salt of3,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrido[1,2-b]isoquinolin-6(2H)-oneand HCl salt of2,2-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrido[1,2-b]isoquinolin-6(2H)-oneas an 85:15 mixture

A flask was charged with a mixture of9-bromo-3,3-dimethyl-3,4-dihydro-1H-pyrido[1,2-b]isoquinolin-6(2H)-oneand9-bromo-2,2-dimethyl-3,4-dihydro-1H-pyrido[1,2-b]isoquinolin-6(2H)-one(55 mg, 0.18 mmol, 1 equiv), 2-ethynylpyridine (0.05 mL, 0.27 mmol, 1.5equiv), Pd(AcO)₂ (4.5 mg, 0.018 mmol, 0.1 equiv), PPh₃ (42 mg, 0.162mmol, 0.9 equiv), CuI (4 mg, 0.018 mmol, 0.1 equiv), Et₃N (0.4 mL) andDMF (5 mL). A vacuum was applied and the reaction mixture was backfilled with nitrogen three times. The mixture was stirred at 70° C. for3.5 h. After the reaction mixture was cooled to room temperature, it wasdiluted with H₂O and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine and dried over anhydroussodium sulfate, then concentrated under reduced pressure and purified bycolumn chromatography to give the title compounds as a mixture.3,3-Dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrido[1,2-b]isoquinolin-6(2H)-oneand2,2-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrido[1,2-b]isoquinolin-6(2H)-onewere obtained in an 85:15 ratio. MS (ESI): 329 (MH⁺). The products werethen converted to the corresponding HCl salts.

3,3-dimethyl-9-(pyridin-2-ylethynyl)-3,4-dihydro-1H-pyrido[1,2-b]isoquinolin-6(2H)-one:MS (ESI): 329 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.87-8.85 (d, J=5.5 Hz,1H), 8.60-8.51 (t, J=8.2 Hz, 1H), 8.39-8.36 (d, J=8.3 Hz, 1H), 8.23-8.21(d, J=8.1 Hz, 1H), 7.99-7.97 (m, 2H), 7.72-7.68 (dd, J=8.4, 1.3 Hz, 1H),6.66 (s, 1H), 3.94 (s, 2H), 2.95-2.91 (t, J=6.8 Hz, 2H), 1.71-1.67 (t,J=7.0 Hz, 2H), 1.06 (s, 6H).

Example 19.1 Synthesis of3-((4-fluorophenyl)ethynyl)-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline

Example 19.1a Synthesis of3-bromo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline

A mixture of3-bromo-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one (200 mg,0.21 mmol, 1.0 equiv) and excess zinc powder, HCl (37%, 1 mL) in MeOH (4mL) was stirred at 75° C. for 30 min. The reaction mixture was pouredinto water (50 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organic layer was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to give the desiredproduct. MS (ESI): 279, 281 (MH+).

Example 19.1b Synthesis of3-((4-fluorophenyl)ethynyl)-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline

The title compound was prepared according to the experimental procedureas described in Example 1.1. MS (ESI): 319 (MH⁺); ¹H NMR (300 MHz,CD₃OD) δ 7.56-7.51 (m, 2H), 7.16-7.10 (m, 3H), 7.86-7.81 (d, J=1.41 Hz,1H), 6.96-6.94 (t, J=7.74 Hz, 1H), 4.68 (s, 2H), 3.50-3.47 (d, J=9.09Hz, 2H), 2.64-2.61 (m, 2H), 1.79-1.76 (m, 6H). mGluR5 PAM EC₅₀: +++.

Example 20.1 Synthesis of (E)-3-methyl-7-styrylquinazolin-4(3H)-one

A solution of 7-bromo-3-methylquinazolin-4(3H)-one (100 mg, 0.42 mmol),styrene (109 mg, 1.05 mmol), Cs₂CO₃ (163.8 mg, 0.5 mmol), Bu₄NBr (135mg, 0.42 mmol), tri(o-tolyl)phosphine (128 mg, 0.42 mmol), and Pd(OAc)₂in DMF (5 mL) was stirred at 100° C. for 3 hours. After it was cooled toroom temperature, the mixture was diluted with H₂O (30 mL) and extractedwith ethyl acetate (2×30 mL). The combined organic layers were washedwith brine and dried over Na₂SO₄. After filtration and concentration,the crude product was purified by column chromatography to give thedesired product (37 mg). MS (ESI): 263 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶)δ 8.37 (s, 1H), 8.15-8.12 (d, J=8.70 Hz, 1H), 7.85-7.82 (m, 2H),7.69-7.67 (d, J=7.26 Hz, 2H), 7.57-7.30 (m, 5H), 3.49 (s, 3H).

Example 20.2 Synthesis of(E)-3-styryl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

A mixture of3-bromo-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one (100 mg,0.34 mmol), Cs₂CO₃ (132.6 mg, 0.85 mmol), Pd(OAc)₂ (30.6 mg, 0.14 mmol),PPh₃ (103 mg, 0.34 mmol), Bu₄NBr (109.5 mg, 0.34 mmol), and styrene(88.7 mg, 0.85 mmol) in DMF (6 mL) in a sealed tube was stirred at 120°C. for two hours. After it was cooled to room temperature, the reactionmixture was quenched with water (20 mL) and extracted with ethyl acetate(3×20 mL). The combined organic layers were dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by silica gelchromatography to give the desired product. MS (ESI): 317 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ 8.08-8.05 (d, J=8.19 Hz, 1H), 7.78-7.74 (m, 2H),7.68-7.66 (m, 2H), 7.54-7.30 (m, 5H), 4.34-4.31 (m, 2H), 3.05 (broad,2H), 1.73-1.70 (m, 6H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: ++.

Example 20.3 Synthesis of(E)-8-methyl-3-(2-(pyridin-2-yl)vinyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

A solution of3-bromo-8-methyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(100 mg, 0.42 mmol), styrene (100 mg, 0.33 mmol), Cs₂CO₃ (128 mg, 0.396mmol), Bu₄NBr (106 mg, 0.33 mmol), PPh₃ (43.2 mg, 0.165 mmol) andPd(OAc)₂ (7.4 mg, 0.033 mmol) in DMF (10 mL) was stirred at 140° C. in asealed tube for 8 hours. After it was cooled to room temperature, themixture was diluted with H₂O and extracted with EtOAc. The combinedorganic layers were washed with brine and dried over Na₂SO₄. Then thefiltration was concentrated and purified by column chromatography togive the desired product. MS (ESI): 332 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.84-8.83 (d, J=5.73 Hz, 1H), 8.68-8.62 (m, 1H), 8.53-8.51 (d, J=8.22Hz, 1H), 8.43-8.41 (d, J=8.37 Hz, 1H), 8.20-8.10 (m, 2H), 8.06 (s, 1H),8.03-7.98 (t, J=13.57 Hz, 1H), 7.74-7.69 (d, J=16.47 Hz, 1H), 5.24-5.17(dd, J=14.92, 6.84 Hz, 1H), 3.95-3.86 (m, 1H), 3.51-3.37 (m, 2H),2.24-2.01 (m, 3H), 1.64-1.52 (m, 1H), 1.45-1.33 (m, 1H), 1.07-1.05 (d,J=6.45 Hz, 3H). mGluR5 PAM EC₅₀: ++.

Example 20.4 Synthesis of(E)-2-methyl-6-styryl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

A solution of6-bromo-2-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (100 mg,0.36 mmol), styrene (75 mg, 0.72 mmol), Pd (PPh₃)₄ (45 mg, 0.036 mmol),PPh₃ (1 mg, 0.0036 mmol) and Et₃N (182 mg, 1.8 mmol) in DMF (10 mL) wasstirred at 140° C. under N₂ for 8 hours. After cooled to roomtemperature, the mixture was diluted with H₂O and extracted with EtOAc.The combined organic layer was washed with brine and dried over Na₂SO₄.Then the filtrate was concentrated and purified by column chromatographyto give the desired product (67 mg). MS (ESI): 303 (MH⁺); ¹H NMR (300MHz, DMSO-d⁶) δ 8.13-8.10 (d, J=8.3 Hz, 1H), 7.87-7.84 (d, J=8.4 Hz,1H), 7.80 (s, 1H), 7.70-7.68 (d, J=7.5 Hz, 2H), 7.56-7.47 (m, 2H),7.44-7.40 (m, 2H), 7.35-7.30 (m, 1H), 4.29-4.22 (dd, J=11.7, 7.8 Hz,1H), 3.68-3.62 (dd, J=11.7, 6.8 Hz, 1H), 3.38-3.29 (dd, J=17.2, 8.1 Hz,1H), 2.91-2.83 (dd, J=17.2, 7.5 Hz, 1H), 2.75-2.67 (m, 1H), 1.18-1.16(d, J=6.7 Hz, 3H). mGluR5 PAM EC₅₀: +++.

Example 20.5 Synthesis of the HCl salt of(E)-2-methyl-6-(2-(pyridin-2-yl)vinyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 20.4. The product was then converted to thecorresponding HCl salt. MS (ESI): 304 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.84-8.83 (d, J=5.4 Hz, 1H), 8.68-8.63 (t, J=8.1 Hz, 1H), 8.54-8.51 (d,J=8.1 Hz, 1H), 8.43-8.40 (d, J=8.3 Hz, 1H), 8.20-8.08 (m, 2H), 8.03-7.99(m, 2H), 7.72-7.67 (d, J=16.6 Hz, 1H), 4.56-4.50 (q, 1H), 3.93-3.87 (q,1H), 3.71-3.63 (dd, J=18.2, 8.5 Hz, 1H), 3.25-3.16 (dd, J=18.3, 7.8 Hz,1H), 3.10-2.96 (m, 1H), 1.36-1.30 (d, J=6.2 Hz, 3H).

Example 20.6 Synthesis of(E)-3-(2-fluorostyryl)-7,7-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

Example 20.6a Synthesis of7,7-dimethyl-3-vinyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-oneand8,8-dimethyl-3-vinyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

A solution of3-bromo-7,7-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one,3-bromo-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one(2.0 g, 6.4 mmol, 1 equiv),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.2 g, 12.8 mmol, 2eq), K₂CO₃ (1.76 g, 12.8 mmol, 2 equiv), Pd(OAc)₂ (576 mg, 2.56 mmol,0.4 equiv) and Ph₃P (1.34 g, 5.12 mmol, 0.8 equiv) in dioxane (200 mL)was stirred at 85° C. for 4 hours under N₂. After that, the reactionmixture was cooled to rt. The reaction was quenched with water (50 mL)and extracted with ethyl acetate (3×50 mL). The combined organic extractwas dried over Na₂SO₄ and concentrated. The crude product was purifiedby silica gel chromatography to afford 650 mg of7,7-dimethyl-3-vinyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-oneand 1.0 g of8,8-dimethyl-3-vinyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one.MS (ESI): 255 (MH⁺).

Example 20.6b Synthesis of(E)-3-(2-fluorostyryl)-7,7-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

A solution of7,7-dimethyl-3-vinyl-8,9-dihydro-6H-pyrido[2,1-1)]quinazolin-11(7H)-one(116 mg, 0.4 mmol, 1 equiv), 1-bromo-2-fluorobenzene (140 mg, 0.8 mmol,2 equiv), Cs₂CO₃ (260 mg, 0.8 mmol, 2 equiv), Pd(OAc)₂ (576 mg, 0.08mmol, 0.2 equiv), Ph₃P (88 mg, 0.32 mmol, 0.8 equiv), Et₃N (80 mg, 0.8mmol, 2 equiv) and (n-Bu)₄NI (256 mg, 0.8 mmol, 2 equiv) in NMP wasstirred at 140° C. for 20 minutes in a microwave reactor. After that,the reaction mixture was cooled to rt. The reaction was quenched withwater (20 mL) and extracted with ethyl acetate (3×20 mL). The organiccombined organic layers were dried over Na₂SO₄ and concentrated. Thecrude was purified by silica gel chromatography to produce 53 mg desiredproduct. MS (ESI): 349 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.20-8.17 (d,J=8.12 Hz, 1H), 7.80-7.68 (m, 2H), 7.56 (s, 1H), 7.43-7.19 (m, 3H),7.15-6.99 (m, 2H), 4.12-3.92 (t, J=13.20 Hz, 2H), 2.82 (s, 2H),1.85-1.72 (t, J=12.84 Hz, 2H), 1.15 (s, 6H). mGluR5 PAM EC₅₀: +++.

Example 20.7. and Example 20.8 Synthesis of the HCl salt of(E)-3-(2-fluorostyryl)-7,7-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one and of HCl salt of(E)-8,8-dimethyl-3-(2-(pyridin-2-yl)vinyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compounds were prepared according to the experimentalprocedure as described in Example 20.4. The products were then convertedto the corresponding HCl salt.

(E)-3-(2-fluorostyryl)-7,7-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

MS (ESI): 332 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.84-8.83 (d, J=5.0 Hz,1H), 8.67-8.62 (t, J=8.1 Hz, 1H), 8.53-8.50 (d, J=9.2 Hz, 1H), 8.44-8.42(d, J=8.4 Hz, 1H), 8.19-8.10 (m, 2H), 8.03-7.98 (m, 2H), 7.72-7.67 (d,J=16.4 Hz, 1H), 4.22-4.18 (t, J=6.4 Hz, 2H), 3.11 (s, 2H), 2.02-1.98 (t,J=6.4 Hz, 2H), 1.23 (s, 6H). mGluR5 PAM EC₅₀: ++++. Fold shift at 10 μM:++.

(E)-8,8-dimethyl-3-(2-(pyridin-2-yl)vinyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

MS (ESI): 332 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.84-8.82 (d, J=5.7 Hz,1H), 8.66-8.61 (t, J=7.9 Hz, 1H), 8.51-8.48 (d, J=8.3 Hz, 1H), 8.44-8.41(d, J=8.4 Hz, 1H), 8.18-8.09 (m, 2H), 8.02-7.98 (m, 2H), 7.72-7.66 (d,J=16.4 Hz, 1H), 3.89 (s, 2H), 3.37-3.32 (t, J=6.7 Hz, 2H), 1.90-1.86 (t,J=6.7 Hz, 2H), 1.19 (s, 6H). Fold shift at 10 μM: +.

Example 20.9 Synthesis of the HCl salt of(E)-6-(2-(7,7-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-3-yl)vinyl)picolinonitrile

A solution of7,7-dimethyl-3-vinyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one(50 mg, 0.2 mmol, 1 equiv), 1-bromo-2-fluorobenzene (70 mg, 0.4 mmol, 2equiv), Cs₂CO₃ (130 mg, 0.4 mmol, 2 equiv), Pd(OAc)₂ (238 mg, 0.04 mmol,0.2 equiv), Ph₃P (44 mg, 0.16 mmol, 0.8 equiv), Et₃N (40 mg, 0.4 mmol, 2equiv), CuI (15 mg, 0.08 mmol, 0.4 equiv) and (n-Bu)₄NI (128 mg, 0.4mmol, 2 equiv) in NMP was stirred at 100° C. over night under N₂. Afterthat, the reaction mixture was cooled to rt. The reaction was quenchedwith water (20 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gelchromatography to produce 20 mg of the desired product. MS (ESI): 357(MH⁺). The product was then converted to the corresponding HCl salt. MS(ESI): 357 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.37-8.34 (d, J=8.40 Hz,1H), 8.11-7.90 (m, 4H), 7.86 (s, 1H), 7.82-7.79 (d, J=16.11 Hz, 1H),7.64-7.59 (d, J=7.41 Hz, 1H), 4.22-4.18 (t, J=6.38 Hz, 2H), 3.12 (s,2H), 2.02-1.98 (t, J=6.42 Hz, 2H), 1.23 (s, 6H). mGluR5 PAM EC₅₀: ++.

Example 20.10 Synthesis of(E)-3-(2-(pyridin-2-yl)vinyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 20.3. MS (ESI): 318 (MH⁺); ¹H NMR (300 MHz,CD₃OD) δ 8.88-8.86 (d, J=5.6 Hz, 1H), 8.69-8.64 (t, J=7.8 Hz, 1H),8.53-8.51 (d, J=8.2 Hz, 1H), 8.45-8.41 (d, J=8.4 Hz, 1H), 8.23-8.12 (m,2H), 8.07-8.00 (m, 2H), 7.76-7.71 (d, J=16.5 Hz, 1H), 4.59-4.56 (m, 2H),3.49-3.40 (m, 2H), 2.06-1.91 (m, 6H). mGluR5 PAM EC₅₀: +++. Fold shiftat 10 μM: +.

Example 20.11 Synthesis of the HCl salt of(E)-8-methyl-3-(2-(pyridin-2-yl)vinyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

The title compound was prepared according to the experimental procedureas described in Example 20.6a and Example 20.6b. The product was thenconverted to the corresponding HCl salt. MS (ESI): 332 (MH⁺).

Example 20.12 Synthesis of(E)-3-(2-fluorostyryl)-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 20.6a. MS (ESI): 349 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.27-8.25 (d, J=8.28 Hz, 1H), 7.73-7.63 (m, 3H), 7.52-7.46 (d,J=16.48 Hz, 1H), 7.30 (s, 1H), 7.24-7.08 (m, 3H), 3.84 (s, 2H),3.07-3.02 (t, J=7.08 Hz, 2H), 1.80-1.75 (t, J=7.80 Hz, 2H), 1.13 (s,6H). mGluR5 PAM EC₅₀: +++.

Example 20.13 Synthesis of the HCl salt of(E)-6-(2-(8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-3-yl)vinyl)picolinonitrile

The title compound was prepared according to the experimental procedureas described in Example 20.6a. The product was then converted to thecorresponding HCl salt. MS (ESI): 357 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ8.37-8.35 (d, J=8.40 Hz, 1H), 8.11-8.08 (dd, J=8.70, 1.50 Hz, 1H),8.04-8.01 (d, J=7.80 Hz, 1H), 7.95-7.90 (d, J=7.98 Hz, 2H), 7.84-7.80(t, J=6.63 Hz, 2H), 7.65-7.59 (d, J=16.09 Hz, 1H), 3.88 (s, 2H),3.38-3.35 (m, 2H), 1.91-1.86 (t, J=6.80 Hz, 2H), 1.20 (s, 6H). mGluR5PAM EC₅₀: ++++.

Example 20.14 Synthesis of6-(3-fluorostyryl)-2,3-dihydro-2-methylpyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 20.4. MS (ESI): 321 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.29-8.26 (d, J=8.3 Hz, 1H), 7.72 (s, 1H), 7.65-7.62 (d, J=8.4Hz, 1H), 7.38-7.34 (m, 2H), 7.31-7.28 (m, 1H), 7.24-7.22 (m, 2H),7.05-6.99 (m, 1H), 4.40-4.34 (dd, J=12.3, 7.5 Hz, 1H), 3.79-3.73 (dd,J=12.3, 6.6 Hz, 1H), 3.35-3.73 (q, 1H), 2.88-2.74 (m, 2H), 1.30-1.28 (d,J=6.6 Hz, 3H). mGluR5 PAM EC₅₀: ++.

Example 21.1 Synthesis of3-phenethyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

A solution of3-(phenylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]-quinazolin-12(6H)-one(50 mg, 0.16 mmol) and Pd(OH)₂/C in CHCl₃ (10 mL) and MeOH (10 mL) wasstirred under H₂ (1 atm) at room temperature for 8 h. The reactionmixture was filtered and the filter cake was washed with water. Thecombined filtrate was extracted with ethyl acetate (3×20 mL) and driedover Na₂SO₄. After filtration and concentration, the residue waspurified by preparative HPLC to give 20 mg of the desired product. MS(ESI): 319 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 7.99-7.97 (d, J=8.10 Hz,1H), 7.40 (s, 1H), 7.38-7.33 (d, J=8.22 Hz, 1H), 7.29-7.17 (m, 5H),4.32-4.29 (t, J=4.98 Hz, 2H), 3.06-2.91 (m, 6H), 1.75 (broad, 4H), 1.68(broad, 2H). mGluR5 PAM EC₅₀: ++.

Example 21.2 Synthesis of8,8-dimethyl-3-(2-(pyridin-2-yl)ethyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 21.1. MS (ESI): 334 (MH⁺).

Example 21.3 Synthesis of3-(2-phenylacetyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

A mixture of3-(phenylethynyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one(400 mg, 1.3 mmol), HgSO₄ (0.1 g, 0.3 mmol, 0.2 equiv) and H₂SO₄ (6 mL)was stirred at room temperature for 2 h. After quenching with water andbasifying with saturated sodium carbonate, the solution was extractedwith ethyl acetate (3×20 mL). The combined organic layers wereconcentrated. The residue was purified by silica gel chromatography togive the desired product (30 mg). MS (ESI): 333 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.22-8.19 (d, J=8.16 Hz, 1H), 8.03-7.99 (d, J=7.14 Hz, 2H),7.59-7.43 (m, 4H), 7.37-7.34 (d, J=8.19 Hz, 1H), 4.40 (s, 2H), 4.39-4.36(t, J=5.34 Hz, 2H), 3.06-3.03 (t, J=3.60 Hz, 2H), 1.85-1.81 (m, 6H).mGluR5 PAM EC₅₀: ++.

Example 21.4 Synthesis of3-(1-hydroxy-2-phenylethyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one

A mixture of3-(2-phenylacetyl)-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one,obtained from Example 21.3 (100 mg, 0.3 mmol) and excess NaBH₄ inCHCl₃/MeOH (10 mL, 1:1) was stirred at room temperature for 2 h. Afterquenching with water, the reaction solution was extracted with ethylacetate (3×20 mL). The combined organic layers were concentrated. Theresidue was purified by silica gel chromatography to give the desiredproduct. MS (ESI): 335 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ: 8.18-8.16 (d,J=8.19 Hz, 1H), 7.82 (s, 1H), 7.41-7.28 (m, 6H), 5.05-5.01 (t, J=7.65Hz, 1H), 4.49-4.46 (t, J=5.01 Hz, 2H), 3.76 (brs, 1H), 3.36-3.33 (t,J=4.08 Hz, 2H), 3.23-3.20 (m, 2H), 2.00-1.86 (m, 6H).

Example 21.5 Synthesis of2-methyl-6-(2-(pyridin-2-yl)ethyl)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 21.1. MS (ESI): 306 (MH⁺). MS (ESI): 306 (MH⁺);¹H NMR (300 MHz, DMSO-d⁶+D₂O) δ 8.76-8.74 (d, J=5.4 Hz, 1H), 8.50-8.45(t, J=6.6 Hz, 1H), 8.06-7.96 (d, J=8.1 Hz, 1H), 7.96-7.94 (d, J=7.8 Hz,1H), 7.91-7.86 (t, J=6.6 Hz, 1H), 7.47 (s, 1H), 7.43-7.41 (d, J=8.1 Hz,1H), 4.25-4.18 (m, 1H), 3.65-3.59 (m, 1H), 3.40-3.35 (t, J=6.6 Hz, 2H),3.30-3.20 (m, 3H), 2.84-2.76 (dd, J=16.8, 7.2 Hz, 1H), 2.70-2.63 (m,1H), 1.14-1.11 (d, J=6.6 Hz, 3H).

Example 21.6 Synthesis of the HCl salt of7,7-dimethyl-3-(2-(pyridin-2-yl)ethyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one

A solution of(E)-7,7-dimethyl-3-(2-(pyridin-2-yl)vinyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one(150 mg, 0.45 mmol) and 10% Pd/C (20 mg) in CH₃OH (20 mL) was stirredunder H₂ (1 atm) at room temperature for 2 h. The reaction mixture wasfiltered and concentrated to give 140 mg of the desired product. MS(ESI): 334 (MH⁺). The product was then converted to the correspondingHCl salt. MS (ESI): 334 (MH⁺); ¹H NMR (300 MHz, CD₃OD) δ 8.80-8.78 (d,J=5.8 Hz, 1H), 8.61-8.55 (t, J=7.9 Hz, 1H), 8.31-8.28 (d, J=8.2 Hz, 1H),8.08-8.05 (d, J=8.0 Hz, 1H), 7.98-7.96 (m, 1H), 7.70-7.67 (d, J=8.1 Hz,2H), 4.20-4.15 (t, J=6.4 Hz, 2H), 3.56-3.51 (m, 2H), 3.43-3.33 (m, 2H),3.11 (s, 2H), 2.01-1.96 (t, J=6.4 Hz, 2H), 1.21 (s, 6H). mGluR5 PAMEC₅₀: +. Fold shift at 10 μM: ++.

Example 21.7 Synthesis of6-(3-fluorophenethyl)-2-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one

The title compound was prepared according to the experimental procedureas described in Example 21.6. MS (ESI): 323 (MH⁺); ¹H NMR (300 MHz,MeOH) δ 8.13-8.10 (d, J=8.9 Hz, 1H), 7.39-7.36 (d, J=7.4 Hz, 2H),7.28-7.21 (m, 1H), 7.00-6.86 (m, 3H), 4.38-4.31 (dd, J=12.0, 7.5 Hz,1H), 3.75-3.69 (dd, J=12.0, 6.9 Hz, 1H), 3.34-3.20 (m, 1H), 3.14-3.00(m, 4H), 2.88-2.72 (m, 2H), 1.27-1.25 (d, J=6.6 Hz, 3H). mGluR5 PAMEC₅₀: +.

Example 22.1 Synthesis of3-methyl-4-oxo-N-(thiazol-2-yl)-3,4-dihydroquinazoline-7-carboxamide

Example 22.1a Synthesis of3-methyl-4-oxo-3,4-dihydroquinazoline-7-carbonyl chloride

A solution of 3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylic acid(110 mg, 0.54 mmol) in SOCl₂ (8 mL) was stirred at reflux for 5 h. Theexcess SOCl₂ was then removed under reduced pressure. The crude3-methyl-4-oxo-3,4-dihydroquinazoline-7-carbonyl chloride was usedwithout further purification for the next step.

Example 22.1b Synthesis of3-methyl-4-oxo-N-(thiazol-2-yl)-3,4-dihydroquinazoline-7-carboxamide

3-methyl-4-oxo-3,4-dihydroquinazoline-7-carbonyl chloride prepared asdescribed in Example 22.1a was dissolved in anhydrous THF and added to asolution of thiazol-2-amine (81 mg, 0.81 mmol) in CHCl₃ (10 mL). Thereaction was stirred at room temperature for 30 min and then poured intowater. The mixture was extracted with ethyl acetate, and the organiclayer was washed with brine, dried over anhydrous sodium sulfate. Afterfiltration and concentration, the crude product was purified by silicagel chromatography purification to provide the desired product. MS(ESI): 287 (MH⁺); ¹H NMR (300 MHz, DMSO-d⁶) δ 12.95 (s, 1H), 8.46 (s,1H), 8.38-8.37 (d, J=1.44 Hz, 1H), 8.29-8.26 (m, 1H), 8.15-8.12 (dd,J=8.36, 1.60 Hz, 1H), 7.60-7.59 (d, J=3.57 Hz, 1H), 7.33-7.32 (d, J=3.45Hz, 1H), 3.53 (s, 3H).

Example 22.2 Synthesis ofN-(4-ethylphenyl)-3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide

The title compound was prepared according to the experimental procedureas described in Example 22.1b. MS (ESI): 308 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 10.47 (s, 1H), 8.47 (s, 1H), 8.28-8.25 (m, 2H), 8.04-8.01 (dd,J=8.30, 1.67 Hz, 1H), 7.72-7.70 (d, J=8.43 Hz, 2H), 7.22-7.19 (d, J=8.43hz, 2H), 3.53 (s, 3H), 2.63-2.55 (q, J=7.58 Hz, 2H), 1.21-1.16 (t,J=7.58 Hz, 3H).

Example 22.3 Synthesis ofN-(1H-benzo[d]imidazol-2-yl)-3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide

The title compound was prepared according to the experimental procedureas described in Example 22.1b. MS (ESI): 320 (MH⁺).

Example 22.4 Synthesis ofN-(4-fluorophenyl)-2-isobutyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide

Example 22.4a Synthesis of methyl2-isobutyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate

A mixture of dimethyl 2-aminoterephthalate (3.0 g, 14.4 mmol),3-methylbutanenitrile (1.2 g, 14.4 mmol), and saturated HCl solution indioxane (20 mL) in sealed tube was stirred at 100° C. overnight. Afterit was cooled to room temperature, the reaction mixture was poured intowater (50 mL) and extracted with ethyl acetate (3×20 mL). The combinedorganic layer was concentrated and the residue was purified by silicagel chromatography give the desired product. MS (ESI): 260 (MH⁺).

Example 22.4b Synthesis of2-isobutyl-4-oxo-3,4-dihydroquinazoline-7-carboxylic acid

A mixture of methyl2-isobutyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (55.8 mg, 0.21mmol), KOH (0.3 g, 5.3 mmol) in water/dioxane (2 mL/5 mL) was stirred atroom temperature for 1 h. The reaction mixture was poured into water (50mL) and the solution was adjusted to pH to 4-5. The mixture wasextracted with ethyl acetate (3×20 mL) and dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by silica gelchromatography to give the desired product. MS (ESI): 246 (MH⁺).

Example 22.4c Synthesis ofN-(4-fluorophenyl)-2-isobutyl-4-oxo-3,4-dihydroquinazoline-7-carboxamide

The title compound was prepared according to the experimental procedureas described in Example 28.1c. MS (ESI): 339 (MH⁺); ¹H NMR (300 MHz,DMSO-d⁶) δ 12.35 (brs, 1H), 10.55 (brs, 1H), 8.21-8.18 (m, 2H),7.96-7.93 (dd, J=8.22, 1.74 Hz, 1H), 7.86-7.81 (dd, J=9.11, 5.15 Hz,2H), 7.24-7.18 (t, J=8.88 Hz, 2H), 2.53 (broad, 2H), 2.27-2.20 (m, 1H),0.97-0.95 (d, J=6.63 Hz, 6H).

Example 23.1 Synthesis of8-methyl-N-(5-methylthiazol-2-yl)-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline-3-carboxamide

Example 23.1a Synthesis of 4-methylcyclohexanone oxime

4-Methylcyclohexanone (2.0 g, 17.8 mmol) was mixed with hydroxylaminehydrochloride (1.86 g, 26.8 mmol) and sodium acetate (2.63 g, 32.0 mmol)in a mixture of EtOH (20 mL) and water (12 mL). The mixture was refluxedfor 5 h. All solvent was removed under reduced pressure and the residuewas partitioned between ethyl acetate and water. After separation, theorganic layer was washed with brine, dried over anhydrous sodiumsulfate. After filtration and concentration, the crude product was usedfor the next step without further purification.

Example 23.1b Synthesis of 5-methylazepan-2-one

4-methylcyclohexanone oxime in 5 mL 80% H₂SO₄ was added dropwise toH₂SO₄ (80%, 5 mL) while stirring and the reaction temperature wasmaintained at 120° C. with an external oil bath. An exotherm wasobserved. After 5 min, the reaction was removed from the oil bath andallowed to cool to room temperature. The reaction mixture was dilutedwith water (30 mL) and adjusted to pH 6 with concentrated NH₄OH. Thissolution was further diluted with water (30 mL) and extracted with DCM(2×25 mL). The combined organic layer was washed with brine, dried overanhydrous sodium sulfate. After filtration and concentration, the crudeproduct (1.6 g) was used for the next step without further purification.

Example 23.1c Synthesis of(E)-7-methoxy-4-methyl-3,4,5,6-tetrahydro-2H-azepine

A mixture of 5-methylazepan-2-one (1.6 g) and dimethyl sulfate (2 g,15.9 mmol) was stirred at 120° C. for 4 h. After it was cooled to roomtemperature, the reaction mixture was diluted with 10 mL ether andadjusted to pH 6 with aqueous KOH. The mixture was extracted with ether(2×50 mL). The organic layer was washed with brine and dried overanhydrous sodium sulfate. After filtration and concentration, the crude(E)-7-methoxy-4-methyl-3,4,5,6-tetrahydro-2H-azepine (1.2 g) was usedfor the next step without further purification.

Example 23.1d Synthesis of8-methyl-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline-3-carboxylicacid

A solution of (E)-7-methoxy-4-methyl-3,4,5,6-tetrahydro-2H-azepine (1.1g) and 2-aminoterephthalic acid (1.4 g, 7.7 mmol) in DMF (30 mL) wasstirred at 100° C. for 4 h. After it was cooled to room temperature, thereaction was diluted with water (80 mL) and extracted with ethyl acetate(2×60 mL). The combined organic layers were washed with brine and driedover anhydrous sodium sulfate. After filtration and concentration, thecrude product was purified by silica gel chromatography to give 47 mg ofdesired product.

Example 23.1e Synthesis of8-methyl-N-(5-methylthiazol-2-yl)-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline-3-carboxamide

The title compound was prepared according to the experimental proceduresas described in Example 22.1. MS (ESI): 369 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 11.44 (broad, 1H), 8.38-8.36 (d, J=8.28 Hz, 1H), 8.18-8.17 (d,J=1.38 Hz, 1H), 7.99-7.95 (dd, J=8.31, 1.53 Hz, 1H), 6.91 (s, 1H),5.22-5.15 (dd, J=14.7, 6.9 Hz, 1H), 3.67-3.59 (m, 1H), 3.17-3.06 (m,2H), 2.39 (s, 3H), 2.25-2.10 (m, 3H), 2.04-1.89 (m, 2H), 1.03-1.01 (d,J=6.60 Hz, 3H). mGluR5 PAM EC₅₀: ++. Fold shift at 10 μM: ++.

Example 23.2 Synthesis ofN-(5-methylthiazol-2-yl)-11-oxo-2,4,5,11-tetrahyrdo-1H-[1,4]oxazepino[5,4-b]quinazoline-8-carboxamide

Example 23.2a Synthesis of 5-methoxy-2,3,6,7-tetrahydro-1,4-oxazepine

A solution of 1,4-oxazepan-5-one (1 g, 8.7 mmol) and (CH₃)₃O⁺BF₄ ⁻ (1.9g, 12.8 mmol) in DCM (30 mL) was stirred at room temperature for 20 h.The reaction mixture was then poured into water (60 mL) and extractedwith DCM (2×50 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate. After filtration and concentration,the crude product was used for the next step without furtherpurification.

Example 23.2b Synthesis of(11-oxo-2,4,5,11-tetrahydro-1H-[1,4]oxazepino[5,4-b]quinazoline-8-carboxylicacid

The title compound was prepared according to the experimental procedureas described in Example 23.1d.

Example 23.2c Synthesis ofN-(5-methylthiazol-2-yl)-11-oxo-2,4,5,11-tetrahyrdo-1H-[1,4]oxazepino[5,4-b]quinazoline-8-carboxamide

The title compound was prepared according to the experimental proceduresas described in Example 22.1. MS (ESI): 357 (MH⁺); ¹H NMR (300 MHz,DMSO-d⁶+D₂O) δ 8.25-8.24 (d, J=1.4 Hz, 1H), 8.23-8.21 (d, J=8.3 Hz, 1H),8.09-8.06 (dd, J=8.3, 1.7 Hz, 1H), 7.25-7.24 (d, J=1.32 Hz, 1H),4.51-4.49 (m, 2H), 3.89-3.87 (t, J=4.8 Hz, 2H), 3.83-3.80 (t, J=4.5 Hz,2H), 3.29-3.26 (t, J=4.8 Hz, 2H), 2.38-2.37 (d, J=1.20 Hz, 3H). mGluR5PAM EC₅₀: ++.

Example 23.3 Synthesis of a mixture ofN-(4-fluorophenyl)-9-methyl-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline-3-carboxamideandN-(4-fluorophenyl)-7-methyl-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline-3-carboxamide

The title compounds were prepared according to the experimentalprocedure as described in Example 23.1a, Example 23.1b, Example 23.1c,Example 23.1d, and Example 22.1a and Example 22.1b. MS (ESI): 366 (MH⁺);Data for the mixture ofN-(4-fluorophenyl)-9-methyl-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline-3-carboxamideandN-(4-fluorophenyl)-7-methyl-12-oxo-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline-3-carboxamide:¹H NMR (300 MHz, CDCl₃) δ 8.33-8.29 (m, 1H), 8.11 (s, 1H), 8.02-8.00 (m,1H), 7.92-7.89 (m, 1H), 7.88-7.63 (m, 2H), 7.13-7.07 (m, 2H), 5.10-4.69(m, 1H), 3.83-3.78 (m, 1H), 3.09-2.98 (m, 2H), 2.03-1.97 (m, 3H),1.68-1.53 (m, 2H), 1.14-1.02 (m, 3H). mGluR5 PAM EC₅₀: +++. Fold shiftat 10 μM: ++.

Example 24.1 Synthesis of4-fluoro-N-(13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazolin-3-yl)benzamide

Example 24.1a Synthesis of3-nitro-8,9,10,11-tetrahydro-6H-azocino[2,1-b]quinazolin-13(7H)-one

The title compound was prepared according to the experimental procedureas described in Example 23.2a and Example 23.2b. MS (ESI): 274 (MH⁺).

Example 24.1b Synthesis of13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide

3-nitro-8,9,10,11-tetrahydro-6H-azocino[2,1-b]quinazolin-13(7H)-one (70mg) was dissolved in MeOH (5 mL). To the solution was added a catalyticamount of Pd/C. The reaction mixture was vacuumed and then back filledwith hydrogen gas three times. The solution was stirred under H₂ (1 atm)for 1h. The reaction mixture was filtered and washed with methanol. Thefiltration was concentrated to give the desired product. MS (ESI): 244(MH⁺).

Example 24.1c Synthesis of4-fluoro-N-(13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazolin-3-yl)benzamide

A solution of 4-fluorobenzoic acid (100 mg, 0.71 mmol) in SOCl₂ (2 mL)was stirred at reflux for 1 h. Excess SOCl₂ was removed and the residuewas dissolved in THF (10 mL). The solution was added to a mixture ofEt₃N (1 mL) and3-amino-8,9,10,11-tetrahydro-6H-azocino[2,1-b]quinazolin-13(7H)-one (22mg, 0.09 mmol). After stirring for 1 h, the mixture was diluted with H₂O(30 mL) and extracted with ethyl acetate (2×30 mL). The combined organiclayers were washed with brine and dried over Na₂SO₄. After filtrationand concentration, the crude product was purified by columnchromatography to give the desired product (2 mg). MS (ESI): 366 (MH⁺);¹H NMR (300 MHz, CDCl₃) δ 8.28 (d, J=8.70 Hz, 1H), 7.96-7.91 (m, 4H),7.75-7.71 (dd, J=8.72 Hz, 2.12 Hz, 1H), 7.24-7.19 (t, J=8.60 Hz, 2H),4.34 (broad, 2H), 3.06-3.02 (m, 2H), 1.99-1.87 (m, 4H), 1.68-1.66 (m,2H), 1.47-1.46 (d, J=4.32 Hz, 2H). mGluR5 PAM EC₅₀: +.

Example 25.1 Synthesis of(E)-6-ethylidene-N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide

Example 25.1a Synthesis of13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylicacid

The title compound was synthesized from 2-aminoterephthalic acidaccording to the experimental procedure as described in Example 23.1cand Example 23.1d. MS (ESI): 273 (MH⁺).

Example 25.1b Synthesis of(E)-6-ethylidene-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylicacid

A solution of13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylicacid (100 mg, 0.37 mmol), acetaldehyde (5 mL) and CH₃COONa (1 g) inacetic acid (10 mL) was stirred at 110° C. for 24 hours. After it wascooled to room temperature, the mixture was adjusted to pH around 8 withNa₂CO₃ and extracted with a mixture of dichloromethane/methanol (10/1)(3×30 mL). The combined organic layers were washed with brine and driedover Na₂SO₄. After filtration and concentration, the crude productobtained was used for the next step without further purification.

Example 25.1c(E)-6-ethylidene-N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide

The title compound was prepared according to the experimental procedureas described in Example 22.1b. MS (ESI): 395 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.44-8.41 (d, J=8.40 Hz, 1H), 8.30-8.27 (d, J=1.71 Hz, 1H),8.03-7.99 (d, J=1.95 Hz, 1H), 6.95 (s, 1H), 5.82-5.80 (q, 1H), 4.33-4.30(t, J=5.7 Hz, 2H), 2.62-2.60 (m, 2H), 2.40 (s, 3H), 1.90-1.87 (d, J=6.8Hz, 4H), 1.71-1.61 (m, 3H), 1.56-1.53 (m, 2H). mGluR5 PAM EC₅₀: +++++.

Example 25.2 Synthesis of6-methylene-N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide

Example 25.2a Synthesis ofN-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide

The title compound was prepared according to the experimental procedureas described in Example 22.1a and Example 22.1b. MS (ESI): 369 (MH⁺).

Example 25.2b Synthesis of6-methylene-N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide

Paraformaldehyde (10 mg),N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide(60 mg, 0.16 mmol) and NaOAc (3 mg, 0.0365 mmol) in 5 mL HOAc wasstirred at 120° C. overnight in a sealed tube. The completion wasmonitored by TLC and LC-MS. The sealed tube was then placed in wateruntil cool. The suspension was diluted with water (30 mL) and adjustedpH to 8, then extracted with ethyl acetate (3×50 mL). The organic phasewas concentrated to give crude product and 20 mg of the desired productwas obtained by column chromatography. MS (ESI): 381 (MH⁺); ¹H NMR (300MHz, CDCl₃) δ 8.45-8.42 (d, J=8.22 Hz, 1H), 8.27 (s, 1H), 8.04-8.00 (dd,J=8.39, 1.61 Hz, 1H), 7.28 (s, 2H), 5.52 (s, 1H), 5.30 (s, 1H),4.39-4.33 (m, 2H). 2.72-2.59 (m, 2H), 2.42 (s, 3H), 1.96-1.88 (m, 2H),1.72-1.68 (m, 2H), 1.56-1.51 (m, 2H).

Example 25.3 Synthesis of6-methyl-N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide

Example 25.3a Synthesis of6-methylene-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylicacid

The title compound was prepared according to the experimental procedureas described in Example 25.1b. MS (ESI): 285 (MH⁺).

Example 25.3b Synthesis of6-methyl-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylicacid

6-methylene-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylicacid (50 mg) was dissolved in MeOH (5 mL). To the mixture was added acatalytic amount of Pd/C. The reaction mixture was vacuumed and thenback filled with hydrogen gas three times. After completion, thereaction was filtered and washed with methanol. The filtrate wasconcentrated to give the desired product. MS (ESI): 287 (MH⁺).

Example 25.3c Synthesis of6-methyl-N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide

The title compound was prepared according to the experimental procedureas described in Example 22.1. MS (ESI): 383 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 8.41-8.38 (d, J=8.37 Hz, 1H), 8.26-8.25 (d, J=1.47 Hz, 1H),8.02-7.98 (dd, J=8.30, 1.68 Hz, 1H), 6.91 (s, 1H), 5.00-4.91 (dt,J=14.1, 3.6 Hz, 1H), 3.98-3.85 (m, 1H), 3.46-3.29 (m, 1H), 2.38 (s, 3H),1.99-1.86 (m, 3H), 1.71-1.61 (m, 5H), 1.49-1.47 (d, J=6.36 Hz, 3H),1.30-1.40 (m, 1H). mGluR5 PAM EC₅₀: ++++.

Example 25.4 Synthesis of6-ethyl-N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide

The title compound was prepared according to the experimental procedureas described in Example 25.1b, Example 25.3b, and Example 22.1a andExample 22.1b. MS (ESI): 397 (MH⁺).

Example 26.1 Synthesis ofN-(4-fluorophenyl)-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide

Example 26.1a Synthesis of13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylicacid

The title compound was prepared according to the experimental procedureas described for Example 23.1d. MS (ESI): 273 (MH⁺).

Example 26.1b Synthesis of7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylic acid

The title compound was prepared according to the experimental procedureas described for Example 19.1a. MS (ESI): 259 (MH+).

Example 26.1c Synthesis ofN-(4-fluorophenyl)-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide

The title compound was prepared according to the experimental procedureas described for Example 28.1c. MS (ESI): 352 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 7.94 (broad, 1H), 7.63-7.58 (m, 3H), 7.43-7.42 (d, J=1.8 Hz,1H), 7.09-7.03 (m, 3H), 4.61 (s, 2H), 3.52-3.48 (t, J=5.7 Hz, 2H),2.61-2.57 (t, J=6.0 Hz, 2H), 1.91-1.87 (m, 2H), 1.76-1.55 (m, 4H).mGluR5 PAM EC₅₀: +.

Example 27.1 Synthesis of3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-8,9,10,11-tetrahydro-6H-azocino[2,1-b]quinazolin-13(7H)-one

Example 27.1a Synthesis of (E)-4-fluoro-N′-hydroxybenzimidamide

To a solution of 4-fluorobenzonitrile (1.21 g, 10 mmol) and NH₂OH.HCl(0.83 g, 12 mmol) in H₂O (5 mL) was added NaHCO₃ in portions. Thereaction mixture was stirred at room temperature overnight. The mixturewas then diluted with H₂O (50 mL) and extracted with ethyl acetate (2×50mL). The combined organic layers were washed with brine and dried overNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure to give the desired product (1.2 g). MS (ESI): 155 (MH⁺).

Example 27.1b Synthesis of3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-8,9,10,11-tetrahydro-6H-azocino[2,1-b]quinazolin-13(7H)-one

A solution of13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylicacid (75 mg, 0.28 mmol) in SOCl₂ (3 mL) was stirred at reflux for 0.5 h.The excess SOCl₂ was removed and the residue was diluted with toluene (5mL). The toluene solution was added dropwise to a solution of(E)-4-fluoro-N-hydroxybenzimidamide (51 mg, 0.33 mmol) in pyridine (2mL). After stirring at room temperature for 0.5 h, the mixture washeated and kept at 60° C. overnight. The reaction mixture wasconcentrated and then diluted with water (25 mL). The aqueous mixturewas extracted with ethyl acetate (2×25 mL). The combined organic layerswere washed with brine and dried over Na₂SO₄. After concentration, thecrude product was purified by column chromatography to give the desiredproduct (13 mg). MS (ESI): 391 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 8.52 (s,1H), 8.45-8.42 (d, J=7.68 Hz, 1H), 8.25-8.18 (m, 3H), 7.23-7.20 (t,J=7.8 Hz, 2H), 4.38 (broad, 2H), 3.11-3.09 (m, 2H), 2.03 (broad, 2H),1.94 (broad, 2H), 1.64 (broad, 2H), 1.48 (broad, 2H).

Example 27.2 Synthesis of3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-8,9,10,11-tetrahydro-6H-azocino[2,1-b]quinazolin-13(7H)-one

Example 27.2a Synthesis of 4-fluorobenzohydrazide

A solution of 4-fluorobenzoic acid (2.8 g, 0.02 mol) in SOCl₂ (6 mL) wasstirred at reflux for 3 h. The reaction mixture was concentrated, thendissolved in MeOH and heated at reflux for 1 h. Hydrazine (20 mL) wasadded to the mixture and heated at reflux overnight. After it was cooledto room temperature, the reaction mixture was filtered to give thedesired product as a white solid (3 g).

Example 27.2b Synthesis of3-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-8,9,10,11-tetrahydro-6H-azocino[2,1-b]quinazolin-13(7H)-one

A solution of13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylicacid (80 mg, 0.28 mmol) in SOCl₂ (3 mL) was stirred at reflux for 0.5 h.The reaction mixture was concentrated and diluted with toluene (5 mL).4-fluorobenzohydrazide (54.4 mg, 0.35 mmol) was added to the solutionand heated to 60° C. After stirring for 1.5 h, the toluene wasevaporated. Phosphoryl trichloride (3 mL) was added to the residue andheated at 80° C. for 1.5 h. Excess phosphoryl trichloride was removedunder reduced pressure and diluted with water (25 mL). The mixture wasadjusted to pH around 7 with aqueous Na₂CO₃ solution. The aqueousmixture was extracted with ethyl acetate (3×20 mL), dried over Na₂SO₄.After filtration, the filtrate was concentrated and purified by columnchromatography to give the desired product (7 mg). MS (ESI): 391 (MH⁺);¹H NMR (300 MHz, CDCl₃) δ 8.43-8.39 (m, 2H), 8.23-8.16 (m, 3H), 7.29 (s,1H), 7.24 (s, 1H), 4.38 (s, 2H), 3.11-3.07 (t, J=6.1 Hz, 2H), 2.05-1.93(m, 4H), 1.65 (m, 2H), 1.49 (broad, 2H).

Example 27.3 Synthesis of3-(4-phenyl-1H-imidazol-1-yl)-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one

A solution of3-bromo-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one(50 mg, 0.17 mmol), 4-phenyl-1H-imidazole (37.4 mg, 0.26 mmol), CuI (8mg, 0.04 mmol) and Cs₂CO₃ in DMF was stirred at 80° C. under nitrogen.The completion of the reaction was monitored by TLC. After thesuspension was diluted with water (30 mL) and extracted with ethylacetate (3×50 mL), the combined organic phases were concentrated tocrude product and 23 mg desired product was obtained by columnchromatography purification. MS (ESI): 357 (MH⁺); MS (ESI): 357 (MH⁺);¹H NMR (300 MHz, CDCl₃) δ 9.15-9.13 (d, J=7.83 Hz, 1H), 8.16 (s, 1H),7.87-7.85 (d, J=7.38 Hz, 2H), 7.72 (s, 1H), 7.57-7.56 (d, J=2.19 Hz,1H), 7.48-7.44 (t, J=7.35 Hz, 2H), 7.38-7.35 (d, J=7.08 Hz, 1H), 7.26(m, 1H), 3.00-2.97 (m, 4H), 1.93-1.91 (m, 2H), 1.79-1.77 (m, 2H),1.71-1.69 (m, 2H).

Example 28.1 Synthesis ofN-(5-methylthiazol-2-yl)-12-oxo-7,8,9,10,11,12-hexahydro-6H-cycloocta[d]pyrido[1,2-a]pyrimidine-3-carboxamide

Example 28.1a Synthesis ofmethyl-12-oxo-7,8,9,10,11,12-hexahydro-6H-cycloocta[d]pyrido[1,2-a]pyrimidine-3-carboxylate

A solution of ethyl 2-oxocyclooctanecarboxylate (1 g, 5.05 mmol) andmethyl 2-aminoisonicotinate (0.768 g, 5.05 mmol) in PPA (2.5 mL) and1,2-dichloroethane (5 mL) was stirred at 85° C. for 18 hours. Thereaction mixture was then cooled to ambient temperature. A chilledsaturated sodium carbonate solution was added to adjust pH to 8. Theresulting mixture was extracted with ethyl acetate (4×100 mL). Thecombined organic layers were washed with brine and dried over anhydroussodium sulfate. After filtration and concentration, the crude productwas purified by silica gel chromatography purification to afford 157 mgof desired product.

Example 28.1b Synthesis of12-oxo-7,8,9,10,11,12-hexahydro-6H-cycloocta[d]pyrido[1,2-a]pyrimidine-3-carboxylicacid

A solution of methyl12-oxo-7,8,9,10,11,12-hexahydro-6H-cycloocta[d]pyrido[1,2-a]-pyrimidine-3-carboxylate(80 mg, 0.28 mmol) and LiOH.H₂O in MeOH (5 mL) was stirred at roomtemperature for 0.5 h. The reaction mixture was adjusted to pH around 6with 1 N HCl and extracted with ethyl acetate (2×25 mL). The combinedethyl acetate layers were washed with brine and dried over anhydroussodium sulfate. After filtration and concentration, the crude productwas used for the next step without further purification.

Example 28.1c Synthesis ofN-(5-methylthiazol-2-yl)-12-oxo-7,8,9,10,11,12-hexahydro-6H-cycloocta[d]pyrido[1,2-a]pyrimidine-3-carboxamide

To a solution of the acid prepared from Example 28.1b and EDCI-HCl (80.2mg, 0.42 mmol) in DCM (10 mL) was added 5-methylthiazol-2-amine (25.5mg, 0.22 mmol). The mixture was stirred at room temperature for 10 minand then poured into 2 N HCl. The mixture was extracted with DCM (30 mL)and the organic layer was washed with aqueous NaHCO₃, brine, dried overanhydrous sodium sulfate. After filtration and concentration, the crudeproduct was purified by preparative HPLC to afford 5.5 mg of desiredproduct. MS (ESI): 369 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 9.09-9.06 (d,J=7.38 Hz, 1H), 8.22 (s, 1H), 7.60-7.58 (d, J=6.57 Hz, 1H), 7.06 (t,J=5.4 Hz, 1H), 3.01-2.93 (m, 4H), 2.44 (s, 3H), 1.92-1.80 (m, 4H), 1.49(broad, 4H). mGluR5 PAM EC₅₀: +++++. Fold shift at 10 μM: +.

Example 28.2 Synthesis ofN-(4-fluorophenyl)-12-oxo-7,8,9,10,11,12-hexahydro-6H-cycloocta[d]pyrido[1,2-a]pyrimidine-3-carboxamide

The title compound was prepared according to the experimental procedureas described in Example 28.1c. MS (ESI): 366 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 9.08-9.05 (d, J=7.47 Hz, 1H), 7.96-7.88 (m, 2H), 7.65-7.58 (m,2H), 7.52-7.48 (dd, J=7.38, 2.01 Hz, 1H), 7.16-7.10 (t, J=8.4 Hz, 2H),3.00-2.87 (m, 4H), 1.96-1.75 (m, 4H), 1.49-1.45 (m, 4H). mGluR5 PAMEC₅₀: +.

Example 28.3 Synthesis ofN-(5-methylthiazol-2-yl)-11-oxo-6,7,8,9,10,11-hexahydrocyclohepta[d]pyrido[1,2-a]pyrimidine-3-carboxamide

The title compound was prepared according to the experimental proceduresas described in Example 28.1. MS (ESI): 355 (MH⁺). mGluR5 PAM EC₅₀: +++.

Example 28.4 Synthesis ofN-(3-methylisoxazol-5-yl)-11-oxo-6,7,8,9,10,11-hexahydrocyclohepta[d]pyrido[1,2-a]pyrimidine-3-carboxamide

The title compound was prepared according to the experimental procedureas described in Example 28.1c. MS (ESI): 339 (MH⁺).

Example 28.5 Synthesis ofN-(3-methylisoxazol-5-yl)-11-oxo-2,3,4,11-tetrahydro-1H-pyrido[2,1-b]quinazoline-7-carboxamide

The title compound was prepared according to the experimental proceduresas described in Example 28.1. MS (ESI): 325 (MH⁺).

Example 29 In vitro cell-based assay for modulation of the activation ofmGluR5 by glutamate

The DNA sequences encoding the structural regions for rat mGluR5 [Abe T,Sugihara H, Nawa H, Shigemoto R, Mizuno N, Nakanishi S (1992) “Molecularcharacterization of a novel metabotropic glutamate receptor mGluR5coupled to inositol phosphate/Ca²⁺ signal transduction” Journal ofBiological Chemistry vol. 267, no. 19, pp. 13361-8] and human mGluR5[Daggett L P, Sacaan A I, Akong M, Rao S P, Hess S D, Liaw C, Urrutia A,Jachec C, Ellis S B, Dreessen J, Knöpfel T, Landwehrmeyer G B, Testa CM, Young A B, Varney M, Johnson E C, Veliçelebi (1995) “Molecular andfunctional characterization of recombinant human metabotropic glutamatereceptor subtype 5” Neuropharmacology vol. 34, no. 8, pp. 871-886] wereprepared synthetically and confirmed by DNA sequencing using standardmethods at Genscript Inc., and inserted using standard molecular biologymethods into the vector pcDNAzeo3.1 (purchased from InvitrogenCorporation). A HEK293 cell line that had previously been created whichstably expresses the rat glial glutamate transporter GLAST (EAAT1)[Schlag B D, Vondrasek J R, Munir M, Kalandadze A, Zelenaia O A,Rothstein J D, Robinson M B (1998) “Regulation of the glialNa+-dependent glutamate transporters by cyclic AMP analogs and neurons”Molecular Pharmacology vol. 53, no. 3, pp. 355-369] was obtained fromDr. Michael Robinson of the Children's Hospital of Philadelphia under aMaterial Transfer Agreement. The pcDNAzeo3.1 vector DNA, carrying eitherrat mGluR5 or human mGluR5, was used to transfect a sample of theHEK293/GLAST cells, and single clones that express mGluR5 were isolatedfrom the transfected cells using zeocin selection. Expression of mGluR5was assessed by measurement of the transient fluorescence signalelicited from HEK293/GLAST/mGluR5 cells by glutamate following theloading of the cells with a calcium-sensitive dye using a FLIPR Tetra(Fluorometric Imaging Plate Reader) (Molecular Devices, Sunnyvale,Calif.) [O'Brien J A, Lemaire W, Chen T B, Chang R S, Jacobson M A, Ha SN, Lindsley C W, Schaffhauser H J, Sur C, Pettibone D J, Conn P J,Williams D L Jr. (2003) “A family of highly selective allostericmodulators of the metabotropic glutamate receptor subtype 5” MolecularPharmacology vol. 64, no. 3, pp. 731-740; Assay Guidance Manual Version5.0, 2008, Eli Lilly and Company and NIH Chemical Genomics Center;available online HEK293/GLAST/mGluR5 cells were grown in Dulbecco'sModified Eagle Medium (DMEM) supplemented with 10% dialyzed fetal bovineserum, 20 millimolar (mM)N-2-hydroxyethylpiperazine-N′-2-ethanesulfonicacid (HEPES), penicillin, streptomycin, 1% GlutaMax™ (Invitrogen) and 50μg/ml zeocin. Cells were grown in the media to 70-80% confluency at 37°C. under 5% CO₂, 95% humidity in poly-D-lysine coated coated flasks.Cells for assays were plated into 96-well sterile standard microtiterplates (pre-coated with poly-D-lysine) at a density of 50,000 cells perwell in 0.2 milliliters of media. Plated cells were allowed to settleand adhere for 30 minutes at ambient conditions, and then were incubatedovernight at 37° C. under 5% CO₂, 95% humidity. Several such 96-wellplates were typically prepared. On the day of the assays, the componentsof the FLIPR calcium 4 assay kit (Molecular Devices) were dissolvedaccording to the instructions of the dye kit's manufacturer in assaybuffer (Hank's balanced salt solution (HBSS) (Gibco) supplemented with20 mM HEPES). After removal of the growth media from the first plate,cells were loaded with calcium dye by addition of calcium dye solution(50 microliters per well) and incubation at 25° C. for 45 to 60 minutes.The first plate was placed into the FLIPR Tetra, and a dilution seriesof glutamate solutions in assay buffer were added to wells on the plate,followed by acquisition of fluorescence data for several minutes. Thefluorescence data (maximal signal as a 4-parameter sigmoidal function oflog [glutamate]) were processed by non-linear regression methods usingthe software package GraphPad Prism 5.01 (GraphPad Software Inc.), toyield a glutamate concentration-response curve (CRC). These resultsallow the calculation of the EC₂₀, EC₅₀, and EC₈₀ values for glutamatefor each day. These values were, respectively, the concentrations ofglutamate that elicit 20%, 50%, and 80% of the maximal FLIPR signal(observed at saturating [glutamate]). The method for measuring theconcentration response of a potentiator, or positive allostericmodulator (PAM), is described here as an example. For that purpose,subsequent assays were typically performed using assay buffer containinga glutamate concentration equal to that day's EC₂₀. The assays of testcompounds to measure activity as positive modulators were typically doneas follows: (1) test compound was added, (2) fluorescence signals weremeasured for 180 seconds, (3) glutamate at its EC₂₀ was added, and (4)fluorescence signals were measured for 120 seconds. For measurement ofthe EC₅₀ value of test compound as a positive modulator of mGluR5, thetest compound was typically added in a volume of 50 microliters as adilution (in assay buffer) of a stock solution of test compound indimethylsulfoxide (DMSO), such that the final concentration of DMSO was0.3% (previously demonstrated to be well tolerated byHEK293/GLAST/mGluR5 for the few minutes required for the assay).Addition to certain wells of the same buffer containing 0.3% DMSO, butwithout any test compound, provided a negative control. Addition tocertain wells of a saturating concentration of glutamate (typically afinal concentration of 15 micromolar) provided a positive control. Themaximal fluorescence signals from the second time interval, from wellscontaining varying concentration of test compound, were analyzed toprovide a CRC for that compound, and yielding a PAM EC₅₀ value andmaximal stimulation value (normalized to that observed for saturatingglutamate) for each test compound. The concentration response curve of areference compound provided a quality control measurement on each plate.

Example 30 Measurement of Glutamate EC₅₀ Shift in the Presence of TestCompounds

Shifts in the EC₅₀ for glutamate caused by the presence of 10 micromolarconcentrations of test compounds (fold shift values) were measured inthe following manner. Preparation of cell plates, incubation with dyeprior to the assay and the FLIPR protocol were as described above. Afterincubation with the dye, the assay plates were transferred to the FLIPR.For each compound tested, sample was added to provide 10 micromolarfinal concentration, and after 180 sec, glutamate was added at varyingconcentrations. The FLIPR signal was monitored for another 120 sec.Three compounds were tested per plate, in duplicate rows, with the top 2rows containing only 0.3% DMSO in buffer, which was the control withoutany test compound. The maximum FLIPR signal after addition of glutamatewas plotted as a function of glutamate concentration, and the EC₅₀values for glutamate were obtained as described above. The ratio ofglutamate EC₅₀ for the control condition (in absence of test compound)to the EC₅₀ in the presence of 10 micromolar test compound was reportedas “glutamate EC₅₀ fold-shift.” Results from assays with cellsexpressing the recombinant human mGluR5 and with cells expressing therecombinant rat mGluR5 were similar but not identical; the values formGluR5 PAM EC₅₀ and fold-shift provided herein were derived solely fromassays performed with cells expressing the recombinant human mGluR5.

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the disclosure and are encompassedby the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated herein by reference in their entireties.Citation or identification of any reference in this application is notan admission that such reference is available as prior art to thisapplication. The full scope of the disclosure is understood withreference to the appended claims.

1. A compound of formula I:

wherein. R¹ is hydrogen, lower alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl,alkylheteroaryl, aryl or heteroaryl, each of which is optionallysubstituted; R² is hydrogen, lower alkyl, lower alkenyl, heteroalkyl,cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl,alkylaryl, alkylheteroaryl, aryl, heteroaryl, —C(O)OR¹², or —CO—NR¹²,each of which is optionally substituted; R³ is hydrogen, lower alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, aryl or heteroaryl,each of which is optionally substituted; or R² and R³ are optionallyjoined, together with the atoms to which they are attached, to form amono or bicyclic ring that is carbocyclic or heterocyclic, each of whichis optionally substituted; G is CHR² or NR² when b and c are both singlebonds, or G is CR² or N when one of b and c is a double bond; Q is NH orCH₂ when d and e are single bonds, or N or CH when one of d or e is adouble bond, or; X is CH or N when f is a single bond, or C when f is adouble bond; Z is CH₂, C═O, C═S or a bond when b is a single bond, or CHor N when b is a double bond; b, c, d, e, and f are each independently asingle bond or a double bond, provided that when b is a double bond, cis a single bond; when c is a double bond, b and d are single bonds;when d is a double bond, c and e are single bonds; when e is a doublebond, d and f are single bonds; and when f is a double bond, e is asingle bond; Y¹, Y² and Y³ are each independently CH, C-halogen, C-loweralkyl, or N, provided that no more than one of Y² and Y³ is N; L¹ is—C≡C—, —HC═CH—, -(lower alkyl)C═C(lower alkyl)-, —CH₂—CH₂—, —CO—CH₂—,—CH(OH)—CH₂, —CH₂—CO—, —C₀₋₆alkyl-O—C₀₋₆alkyl-, —NR¹²SO—, —SONR¹²—,—NR¹²SO₂—, —SO₂NR¹²—, —NR¹²—CO—, —CO—NR¹²—,

R¹² is hydrogen or lower alkyl; W¹ and W² are each independently N orCH; W³ is O, S or NR⁴; and R⁴ is hydrogen or lower alkyl; or apharmaceutically acceptable salt thereof; provided that at least one ofc and d is a double bond.
 2. The compound of claim 1, wherein thecompound is of formula Ia:

wherein R^(1a) is aryl, heteroaryl or cycloalkyl, each of which isoptionally substituted; L^(1a) is —C≡C—, —HC═CH—, —CH₂CH₂—, —C(O)NH—,—NHC(O)—, CH(OH)CH₂—, C(O)CH₂,

Y^(1a), Y^(2a) and Y^(3a) are each independently CH, N, or C-halogen,provided that no more than one of Y^(2a) and Y^(3a) is N; c, d e, and fare each independently single or double bonds; provided that when c is adouble bond, d is a single bond; when d is a double bond, c and e aresingle bonds; when e is a double bond, d and f are single bonds; andwhen f is a double bond, e is a single bond; X^(a) is N when f is asingle bond or C when f is a double bond; Q^(a) is NH when d and e aresingle bonds or N or CH when one of d or e is a double bond; Z^(a) isC═O or CH₂; G^(a) is NR^(2a) when c is a single bond, or G^(a) isCR^(2a) when c is a double bond; R^(2a) is hydrogen, lower alkyl, loweralkenyl, heteroalkyl, —C(O)R^(12a), —CONR^(12a), or cycloalkyl, each ofwhich is optionally substituted; R^(3a) is hydrogen, lower alkyl,cycloalkyl, heteroalkyl, or heterocycloalkyl, each of which isoptionally substituted; or R^(2a) and R^(3a), together with the atoms towhich they are attached are linked to form a mononcyclic or bicycliccycloalkyl or heterocyclic ring, each of which is optionallysubstituted; and R^(12a) is hydrogen or lower alkyl. In someembodiments, at least one of G^(a), Q^(a), and X^(a) is N. In someembodiments, at least two of G^(a), Q^(a), and X^(a) is N. In someembodiments, both Q^(a) and G^(a) are N. In some embodiments, both Q^(a)and X^(a) are N.
 3. The compound of claim 1 or 2, wherein L¹ is —C≡C— or—HC═CH—.
 4. The compound of claim 1 or 2, wherein either Q and X or Qand G are both N.
 5. The compound of claim 2, wherein R^(1a) is aryl. 6.The compound of claim 5, wherein R^(1a) is selected from


7. The compound of claim 2, wherein R^(1a) is heteroaryl.
 8. Thecompound of claim 7, wherein R^(1a) is selected from


9. The compound of claim 2, wherein R^(1a) is cycloalkyl.
 10. Thecompound of claim 9, wherein R^(1a) is selected from


11. The compound of claim 2, wherein R^(2a) is lower alkyl.
 12. Thecompound of claim 11, wherein R^(2a) is selected from methyl, propyl,cyclopropylmethyl, isobutyl and sec-butyl.
 13. The compound of claim 2,wherein R^(2a) is lower alkenyl.
 14. The compound of claim 11, whereinR^(2a) is CH₂═CH—.
 15. The compound of claim 2, wherein R^(2a) isheteroalkyl.
 16. The compound of claim 15, wherein R^(2a) is selectedfrom methoxymethyl, hydroxymethyl, methoxyethyl, hydroxyethyl,ethoxymethyl, ethoxyethyl,


17. The compound of claim 2, wherein R^(2a) is cycloalkyl.
 18. Thecompound of claim 17, wherein R^(2a) is


19. The compound of claim 2, wherein R^(2a) is heterocycloalkyl-loweralkyl.
 20. The compound of claim 19, wherein R^(2a) is selected from


21. The compound of claim 2, wherein R^(2a) is heteroarylalkyl.
 22. Thecompound of claim 21, wherein R^(2a) is


23. The compound of claim 2, wherein R^(2a) is —C(O)OR^(12a).
 24. Thecompound of claim 23, wherein R^(12a) is methyl.
 25. The compound ofclaim 2, wherein R^(2a) is —CO—NR^(12a).
 26. The compound of claim 25,wherein R^(12a) is ethyl.
 27. The compound of claim 2, wherein R^(3a) isheterocycloalkyl.
 28. The compound of claim 27, wherein R^(3a) isselected from


29. The compound of claim 2, wherein R^(3a) is cycloalkyl.
 30. Thecompound of claim 29, wherein R^(3a) is


31. The compound of claim 2, wherein R^(3a) is heteroalkyl.
 32. Thecompound of claim 31, wherein R^(3a) is selected from methoxymethyl,methoxyethyl, dimethylaminoethyl, dimethylaminomethyl,


33. The compound of claim 2, wherein R^(3a) is lower alkyl.
 34. Thecompound of claim 33, wherein R^(3a) is isobutyl or sec-butyl.
 35. Thecompound of claim 2, wherein R^(2a) and R^(3a), together with the atomsto which they are attached are linked to form a mononcyclic or bicyclicring that is cycloalkyl or heterocyclic.
 36. The compound of claim 35,wherein R^(2a) and R^(3a) are linked to form a ring selected from:


37. A compound that is selected from:


38. A pharmaceutical composition comprising a compound of claim 1 or 37and a pharmaceutically acceptable carrier.
 39. A method of treating orameliorating a neurological disorder, comprising administering atherapeutically effective amount of a compound of claim 1 or
 37. 40. Themethod of claim 39, wherein the neurological disorder is selected fromneurodegenerative diseases, neuropsychiatric diseases, affectivedisorders, and loss of cognitive function, learning and memorydisorders.
 41. A method of claim 39, wherein the neurological disorderis selected from schizophrenia, psychosis, and a cognitive disorder. 42.The method of claim 39, wherein the neurological disorder isschizophrenia.
 43. The method of claim 39, wherein the neurologicaldisorder is psychosis.
 44. The method of claim 39, wherein theneurological disorder is a cognitive disorder.
 45. The method of claim39, wherein the neurological disorder is Alzheimer's disease.